Mitochondrial Medicine

Also see:
Protect the Mitochondria
Carbon Dioxide as an Antioxidant
Promoters of Efficient v. Inefficient Metabolism
ATP Regulates Cell Water
Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
High Cholesterol and Metabolism
Mitochondria and mortality
Mitochondrial medicine
Low Blood Sugar Basics
The Cholesterol and Thyroid Connection
Thyroid Status and Oxidized LDL
The Truth about Low Cholesterol
Hypothyroidism and A Shift in Death Patterns
Light is Right
Using Sunlight to Sustain Life
PUFA Decrease Cellular Energy Production
PUFA Breakdown Products Depress Mitochondrial Respiration
“Curing” a High Metabolic Rate with Unsaturated Fats
Power Failure: Does mitochondrial dysfunction lie at the heart of common, complex diseases like cancer and autism?
Faulty Energy Production in Brain Cells Leads to Disorders Ranging from Parkinson’s to Intellectual Disability

Diabetologia. 2008 May; 51(5): 697–699.
Professor Rolf Luft, 1914–2007
P.-O. Berggren and K. Brismar

J Clin Invest. 1962 Sep;41:1776-804.
A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study.

J Intern Med. 1995 Nov;238(5):405-21.
Mitochondrial medicine
Luft R, Landau BR.
In the mitochondrion, inherited defects have been identified in the electron transport system by which ATP is formed, as well as in the transport and metabolism of fuels. Clinical findings in diseases due to these defects can be related to abnormal accumulations of metabolic intermediates and inadequate or inefficient ATP generation. In the oxidative process within the mitochondrion, chemical oxidants are generated, which can cause cellular damage. As the body’s defences against the oxidants decline, oxidative damage appears to contribute to the ageing process itself as well as to age-related degenerative diseases. Understanding in this area has accelerated with knowledge of the synthesis, structure and function of the mitochondrion and its specific DNA. The frontier is expected to advance rapidly as causal relationships between these diseases and mitochondrial dysfunction, and the potential role of antioxidants in therapy, are better defined.

Biochim Biophys Acta. 1995 May 24;1271(1):1-6.
The development of mitochondrial medicine.
Luft R.
I consider mitochondrial medicine a tentative designation for an area within clinical medicine still to be delineated. Its development extends over a period of 35 years, from its discovery in 1959 [1]. Progress had been gradual until recent years when it has become explosive in nature with extensions in many different directions. My presentation is an effort to illustrate this evolution with emphasis on especially important observations which by leaps advanced the area. We are fortunate to have here several of the distinguished investigators, who have contributed so much to those advances. They will share with us their deep knowledge in different aspects of mitochondrial medicine, what is known, what remains to be elucidated, and what the problems are to be encountered in that elucidation.

Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8731-8.
The development of mitochondrial medicine.
Luft R.
Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect–a myopathy–was demonstrated only 35 years ago. The field’s dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.

J Inherit Metab Dis. 2011 April; 34(2): 247–248.
Mitochondrial medicine
Saskia Koene and Jan Smeitink
“Almost 50 years after the first description of a patient with a mitochondrial disease (Luft et al. 1962), there now is an extraordinarily rapid development in mitochondrial medicine. In the first 30 years of mitochondrial disease research, the focus was centered on unravelling the aetiology of the high variety of manifestations of mitochondrial dysfunction.”

J Intern Med. 2009 Feb;265(2):193-209. doi: 10.1111/j.1365-2796.2008.02058.x.
Mitochondrial medicine: entering the era of treatment.
Koene S, Smeitink J.
Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led to a better understanding of mitochondrial biology in health and disease. The obtained knowledge is of increasing importance for physicians of all medical disciplines. It assists in enabling the development of rational treatment strategies for diseases or conditions caused by mitochondrial dysfunction. The still frequently used classical interventions with vitamins or co-factors are only beneficial in some rare mitochondrial disease conditions, like coenzyme Q biosynthesis defects. For that reason alternative strategies to correct disturbed energy metabolism have to be developed. New approaches in this direction include nutrition and exercise therapies, alternative gene expression, enzyme-replacement, scavenging of potentially toxic compounds and modulating cell signalling. The effect of some of these interventions has already been explored in humans whilst others are still at the level of single cell research. We review the state of the art of the development of mitochondrial treatment strategies and discuss what steps need to be taken to efficiently approach the huge burden of disease caused by dysfunctional mitochondria.

J Am Diet Assoc. 2003 Aug;103(8):1029-38.
Nutritional cofactor treatment in mitochondrial disorders.
Marriage B, Clandinin MT, Glerum DM.
Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5′-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented.

Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1561-7. doi: 10.1016/j.addr.2008.05.001. Epub 2008 Jul 4.
The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies.
Tarnopolsky MA.
Mitochondrial cytopathies ultimately lead to a reduction in aerobic energy transduction, depletion of alternative energy stores, increased oxidative stress, apoptosis and necrosis. Specific combinations of nutraceutical compounds can target many of the aforementioned biochemical pathways. Antioxidants combined with cofactors that can bypass specific electron transport chain defects and the provision of alternative energy sources represents a specific targeted strategy. To date, there has been only one randomized double-blind clinical trial using a combination nutraceutial therapy and it showed that the combination of creatine monohydrate, coenzyme Q10, and alpha-lipoic acid reduced lactate and markers of oxidative stress in patients with mitochondrial cytopathies. Future studies need to use larger numbers of patients with well defined clinical and surrogate marker outcomes to clarify the potential role for combination nutraceuticals (“mitochondrial cocktail”) as a therapy for mitochondrial cytopathies.

Muscle Nerve. 2007 Feb;35(2):235-42.
Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.
Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA.
Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

Annu Rev Biochem. 2010;79:683-706. doi: 10.1146/annurev-biochem-060408-093701.
Somatic mitochondrial DNA mutations in mammalian aging.
Larsson NG.
Mitochondrial dysfunction is heavily implicated in the multifactorial aging process. Aging humans have increased levels of somatic mtDNA mutations that tend to undergo clonal expansion to cause mosaic respiratory chain deficiency in various tissues, such as heart, brain, skeletal muscle, and gut. Genetic mouse models have shown that somatic mtDNA mutations and cell type-specific respiratory chain dysfunction can cause a variety of phenotypes associated with aging and age-related disease. There is thus strong observational and experimental evidence to implicate somatic mtDNA mutations and mosaic respiratory chain dysfunction in the mammalian aging process. The hypothesis that somatic mtDNA mutations are generated by oxidative damage has not been conclusively proven. Emerging data instead suggest that the inherent error rate of mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma) may be responsible for the majority of somatic mtDNA mutations. The roles for mtDNA damage and replication errors in aging need to be further experimentally addressed.

J Intern Med. 2008 Feb;263(2):167-78. doi: 10.1111/j.1365-2796.2007.01905.x.
Mitochondrial dysfunction as a cause of ageing.
Trifunovic A, Larsson NG.
Mitochondrial dysfunction is heavily implicated in the ageing process. Increasing age in mammals correlates with accumulation of somatic mitochondrial DNA (mtDNA) mutations and decline in respiratory chain function. The age-associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA mutator mice has shown that increased levels of somatic mtDNA mutations directly can cause a variety of ageing phenotypes, such as osteoporosis, hair loss, greying of the hair, weight reduction and decreased fertility. Respiratory-chain-deficient cells are apoptosis prone and increased cell loss is therefore likely an important consequence of age-associated mitochondrial dysfunction. There is a tendency to automatically link mitochondrial dysfunction to increased generation of reactive oxygen species (ROS), however, the experimental support for this concept is rather weak. In fact, respiratory-chain-deficient mice with tissue-specific mtDNA depletion or massive increase of point mutations in mtDNA typically have minor or no increase of oxidative stress. Mitochondrial dysfunction is clearly involved in the human ageing process, but its relative importance for mammalian ageing remains to be established.

Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):961-7. doi: 10.1016/j.bbabio.2010.01.004. Epub 2010 Jan 11.
Mitochondrial energy metabolism and ageing.
Bratic I, Trifunovic A.
Ageing can be defined as “a progressive, generalized impairment of function, resulting in an increased vulnerability to environmental challenge and a growing risk of disease and death”. Ageing is likely a multifactorial process caused by accumulated damage to a variety of cellular components. During the last 20 years, gerontological studies have revealed different molecular pathways involved in the ageing process and pointed out mitochondria as one of the key regulators of longevity. Increasing age in mammals correlates with increased levels of mitochondrial DNA (mtDNA) mutations and a deteriorating respiratory chain function. Experimental evidence in the mouse has linked increased levels of somatic mtDNA mutations to a variety of ageing phenotypes, such as osteoporosis, hair loss, graying of the hair, weight reduction and decreased fertility. A mosaic respiratory chain deficiency in a subset of cells in various tissues, such as heart, skeletal muscle, colonic crypts and neurons, is typically found in aged humans. It has been known for a long time that respiratory chain-deficient cells are more prone to undergo apoptosis and an increased cell loss is therefore likely of importance in the age-associated mitochondrial dysfunction. In this review, we would like to point out the link between the mitochondrial energy balance and ageing, as well as a possible connection between the mitochondrial metabolism and molecular pathways important for the lifespan extension.

Chang Gung Med J. 2009 Mar-Apr;32(2):113-32.
Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging.
Wei YH, Wu SB, Ma YS, Lee HC.
Aging is a biological process that is characterized by the gradual loss of physiological function and increases in the susceptibility to disease of an individual. During the aging process, a wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) has been observed in somatic tissues of humans and animals. This is associated with the decline in mitochondrial respiratory function; excess production of the reactive oxygen species (ROS); increase in the oxidative damage to mtDNA, lipids and proteins in mitochondria; accumulation of point mutations and large-scale deletions of mtDNA; and altered expression of genes involved in intermediary metabolism. It has been demonstrated that the ROS may cause oxidative damage and mutations of mtDNA and alterations of the expression of several clusters of genes in aging tissues and senescent cells. We found that intracellular levels of hydrogen peroxide (H2O2) and oxidative damage to DNA in the tissue cells and skin fibroblasts of old donors were higher than those of young donors. In H2O2-induced senescent skin fibroblasts, we observed an increase in the protein expression and activity levels of manganese-dependent superoxide dismutase and a concurrent decrease in the activity of cytochrome c oxidase and the rate of oxygen consumption. Moreover, the mRNA and protein expression levels of pyruvate dehydrogenase (PDH) were decreased but those of PDH kinase and lactate dehydrogenase were increased in senescent skin fibroblasts. The changes in the expression of these enzymes suggest a metabolic shift from mitochondrial respiration to glycolysis as a major supply of ATP in aging human cells. On the other hand, recent studies on mitochondrial mutant mice, which carry a proofreading deficient subunit of DNA polymerase gamma, revealed that mtDNA mutations accumulated in somatic tissues in the mice that displayed prominent features of aging. Taken together, we suggest that the respiratory function decline and increase in the production of the ROS in mitochondria, accumulation of mtDNA mutation and oxidative damage, and altered expression of a few clusters of genes that culminated in the metabolic shift from mitochondrial respiration to glycolysis for major supply of ATP were key contributory factors in the aging process in the human and animals.

Zhonghua Yi Xue Za Zhi (Taipei). 2001 May;64(5):259-70.
Mitochondrial theory of aging matures–roles of mtDNA mutation and oxidative stress in human aging.
Wei YH, Ma YS, Lee HC, Lee CF, Lu CY.
Mitochondrial theory of aging, a variant of free radical theory of aging, proposes that accumulation of damage to mitochondria and mitochondrial DNA (mtDNA) leads to aging of humans and animals. It has been supported by the observation that mitochondrial function declines and mtDNA mutation increases in tissue cells in an age-dependent manner. Age-related impairment in the respiratory enzymes not only decreases ATP synthesis but also enhances production of reactive oxygen species (ROS) through increased electron leakage in the respiratory chain. Human mtDNA, which is not protected by histones and yet is exposed to high levels of ROS and free radicals in the matrix of mitochondria, is susceptible to oxidative damage and mutation in tissue cells. In the past decade, more than one hundred mtDNA mutations have been found in patients with mitochondrial disease, and some of them also occur in aging human tissues. The incidence and abundance of these mutant mtDNAs are increased with age, particularly in tissues with great demand for energy. On the other hand, recent studies have revealed that the ability of the human cell to cope with oxidative stress is compromised in aging. Comparative analysis of gene expression by microarray technology has shown that a number of genes related to oxidative stress response are altered in aging animals. We discovered that the transcripts of early growth response protein-1, growth arrest and DNA damage-inducible proteins and glutathione S-transferase genes are increased in response to oxidative stress in human skin fibroblasts. Moreover, the activities of Cu,Zn-SOD, catalase and glutathione peroxidase decrease with age, whereas Mn-SOD activity increases with age up to 65 years and slightly declines thereafter in skin fibroblasts. Such an imbalance in the function of antioxidant enzymes may result in excess production of damaging ROS in the cell. This notion is supported by the observation that intracellular levels of H2O2 and oxidative damage to DNA and lipids are significantly increased with age of the fibroblast donor. Furthermore, the mitochondrial pool of reduced glutathione declines and DNA damage is enhanced in aging tissues. Taken together, these observations and our previous findings that mtDNA mutations and oxidative damage are increased in aging human tissues suggest that mitochondrial theory of aging is mature.

Nutr Res. 2008 Mar;28(3):172-8. doi: 10.1016/j.nutres.2008.01.001.
Long-term creatine supplementation is safe in aged patients with Parkinson disease.
Bender A, Samtleben W, Elstner M, Klopstock T.
The food supplement creatine (Cr) is widely used by athletes as a natural ergogenic compound. It has also been increasingly tested in neurodegenerative diseases as a potential neuroprotective agent. Weight gain is the most common side effect of Cr, but sporadic reports about the impairment of renal function cause the most concerns with regard to its long-term use. Data from randomized controlled trials on renal function in Cr-supplemented patients are scarce and apply mainly to healthy young athletes. We systematically evaluated potential side effects of Cr with a special focus on renal function in aged patients with Parkinson disease as well as its current use in clinical medical research. Sixty patients with Parkinson disease received either oral Cr (n = 40) or placebo (n = 20) with a dose of 4 g/d for a period of 2 years. Possible side effects as indicated by a broad range of laboratory blood and urine tests were evaluated during 6 follow-up study visits. Overall, Cr was well tolerated. Main side effects were gastrointestinal complaints. Although serum creatinine levels increased in Cr patients because of the degradation of Cr, all other markers of tubular or glomerular renal function, especially cystatin C, remained normal, indicating unaltered kidney function. The data in this trial provide a thorough analysis and give a detailed overview about the safety profile of Cr in older age patients.

Ann N Y Acad Sci. 1998 Nov 20;854:155-70.
Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function.
Wei YH, Lu CY, Lee HC, Pang CY, Ma YS.
Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age-dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA-binding proteins, is susceptible to oxidative damage by the ever-increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8-hydroxy-2′-deoxyguanosine) and large-scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA-encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age-dependent progression of the clinical course of mitochondrial diseases.

Exp Biol Med (Maywood). 2007 May;232(5):592-606.
Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging.
Lee HC, Wei YH.
A wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) with aging has been observed in animals and humans. These include (i) decline in mitochondrial respiratory function; (ii) increase in mitochondrial production of reactive oxygen species (ROS) and the extent of oxidative damage to DNA, proteins, and lipids; (iii) accumulation of point mutations and large-scale deletions of mtDNA; and (iv) enhanced apoptosis. Recent studies have provided abundant evidence to substantiate the importance of mitochondrial production of ROS in aging. On the other hand, somatic mtDNA mutations can cause premature aging without increasing ROS production. In this review, we focus on the roles that ROS play in the aging-associated decline of mitochondrial respiratory function, accumulation of mtDNA mutations, apoptosis, and alteration of gene expression profiles. Taking these findings together, we suggest that mitochondrial dysfunction, enhanced oxidative stress, subsequent accumulation of mtDNA mutations, altered expression of a few clusters of genes, and apoptosis are important contributors to human aging.

Biochim Biophys Acta. 2009 Oct;1790(10):1021-9. doi: 10.1016/j.bbagen.2009.04.012. Epub 2009 May 4.
Response to the increase of oxidative stress and mutation of mitochondrial DNA in aging.
Ma YS, Wu SB, Lee WY, Cheng JS, Wei YH.
In the aging process, mitochondrial function gradually declines with an increase of mutations in mitochondrial DNA (mtDNA) in tissue cells. Some of the aging-associated mtDNA mutations have been shown to result in not only inefficient generation of ATP but also increased production of reactive oxygen species (ROS) such as superoxide anions (O2-) and hydrogen peroxide (H2O2) in the mitochondria of aging tissues. Extensive studies have revealed that such an increase of oxidative stress is a contributory factor for alterations in the expression and activities of antioxidant enzymes and increased oxidative damage to DNA, RNA, proteins, and lipids in tissues and cultured cells from elderly subjects. Recently, we observed that gene expression of several proteins and enzymes related to iron metabolism is altered and that aconitase is extremely susceptible to oxidative damage in senescent skin fibroblasts and in cybrids harboring aging-associated A8344G mutation of mtDNA. Of great importance is the perturbation at the protein and activity levels of several enzymes containing iron-sulfur clusters in skin fibroblasts of elderly subjects. Taken together, these findings suggest that cellular response to oxidative stress and oxidative damage elicited by mitochondrial dysfunction and/or mtDNA mutations plays an important role in human aging.

Chin J Physiol. 2001 Mar 31;44(1):1-11.
Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system.
Wei YH, Lu CY, Wei CY, Ma YS, Lee HC.
Respiratory function of mitochondria is compromised in aging human tissues and severely impaired in the patients with mitochondrial disease. A wide spectrum of mitochondrial DNA (mtDNA) mutations has been established to associate with mitochondrial diseases. Some of these mtDNA mutations also occur in various human tissues in an age-dependent manner. These mtDNA mutations cause defects in the respiratory chain due to impairment of the gene expression and structure of respiratory chain polypeptides that are encoded by the mitochondrial genome. Since defective mitochondria generate more reactive oxygen species (ROS) such as O2- and H2O2 via electron leak, we hypothesized that oxidative stress is a contributory factor for aging and mitochondrial disease. This hypothesis has been supported by the findings that oxidative stress and oxidative damage in tissues and culture cells are increased in elderly subjects and patients with mitochondrial diseases. Another line of supporting evidence is our recent finding that the enzyme activities of Cu,Zn-SOD, catalase and glutathione peroxidase (GPx) decrease with age in skin fibroblasts. By contrast, Mn-SOD activity increases up to 65 years of age and then slightly declines thereafter. On the other hand, we observed that the RNA, protein and activity levels of Mn-SOD are increased two- to three-fold in skin fibroblasts of the patients with CPEO syndrome but are dramatically decreased in patients with MELAS or MERRF syndrome. However, the other antioxidant enzymes did not change in the same manner. The imbalance in the expression of these antioxidant enzymes indicates that the production of ROS is in excess of their removal, which in turn may elicit an elevation of oxidative stress in the fibroblasts. Indeed, it was found that intracellular levels of H2O2 and oxidative damage to DNA and lipids in skin fibroblasts from elderly subjects or patients with mitochondrial diseases are significantly increased as compared to those of age-matched controls. Furthermore, Mn-SOD or GPx-1 gene knockout mice were found to display neurological disorders and enhanced oxidative damage similar to those observed in the patients with mitochondrial disease. These observations are reviewed in this article to support that oxidative stress elicited by defective respiratory function and impaired antioxidant enzyme system plays a key role in the pathophysiology of mitochondrial disease and human aging.

Aging (Albany NY). 2012 Dec;4(12):859-60.
Mitochondria, obesity and aging.
Vernochet C, Kahn CR.
Among the many factors contributing to aging, one of the most highly investigated focuses on the theory that there is a gradually decline of mitochondrial function with age leading to progressive tissue damage via oxidative stress (Figure ​(Figure1,1, right). Indeed, proper mitochondrial function is required for normal metabolism and health at multiple levels. Mutations in mitochondrial DNA (mtDNA) result in a variety of phenotypes including myopathies, neuropathies, diabetes, signs of premature aging and reduced lifespan [1,2]. Mitochondrial dysfunction in the absence of somatic mutations is also a feature of normal aging and has been observed in species ranging from worms to humans. At the organ level, mitochondrial dysfunction occurs in many age-related diseases, including type 2 diabetes and obesity. In both rodents and humans, obesity and type 2 diabetes are associated reduced expression of mtDNA and reduced levels of proteins involved in oxidative phosphorylation in muscle, liver and adipose tissue [3]. Conversely, caloric restriction, which increases mitochondria biogenesis and maintains mitochondrial function, is associated with increased longevity [2].

Ageing Res Rev. 2010 Jan;9(1):20-40. doi: 10.1016/j.arr.2009.09.006. Epub 2009 Oct 1.
Compromised respiratory adaptation and thermoregulation in aging and age-related diseases.
Chan SL, Wei Z, Chigurupati S, Tu W.
Mitochondrial dysfunction and reactive oxygen species (ROS) production are at the heart of the aging process and are thought to underpin age-related diseases. Mitochondria are not only the primary energy-generating system but also the dominant cellular source of metabolically derived ROS. Recent studies unravel the existence of mechanisms that serve to modulate the balance between energy metabolism and ROS production. Among these is the regulation of proton conductance across the inner mitochondrial membrane that affects the efficiency of respiration and heat production. The field of mitochondrial respiration research has provided important insight into the role of altered energy balance in obesity and diabetes. The notion that respiration and oxidative capacity are mechanistically linked is making significant headway into the field of aging and age-related diseases. Here we review the regulation of cellular energy and ROS balance in biological systems and survey some of the recent relevant studies that suggest that respiratory adaptation and thermodynamics are important in aging and age-related diseases.

Nutr Rev. 2009 Aug;67(8):427-38. doi: 10.1111/j.1753-4887.2009.00221.x.
Electron transfer mediators and other metabolites and cofactors in the treatment of mitochondrial dysfunction.
Orsucci D, Filosto M, Siciliano G, Mancuso M.
Mitochondrial disorders (MDs) are caused by impairment of the mitochondrial electron transport chain (ETC). The ETC is needed for oxidative phosphorylation, which provides the cell with the most efficient energy outcome in terms of ATP production. One of the pathogenic mechanisms of MDs is the accumulation of reactive oxygen species. Mitochondrial dysfunction and oxidative stress appear to also have a strong impact on the pathogenesis of neurodegenerative diseases and cancer. The treatment of MDs is still inadequate. Therapies that have been attempted include ETC cofactors, other metabolites secondarily decreased in MDs, antioxidants, and agents acting on lactic acidosis. However, the role of these dietary supplements in the treatment of the majority of MDs remains unclear. This article reviews the rationale for their use and their role in clinical practice in the context of MDs and other disorders involving mitochondrial dysfunction.

Mol Genet Metab. 2004 Apr;81(4):263-72.
Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders.
Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM.
Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Mitochondrion. 2007 Jun;7 Suppl:S136-45. Epub 2007 Mar 30.
The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease.
Haas RH.
The evidence supporting a treatment benefit for coenzyme Q10 (CoQ10) in primary mitochondrial disease (mitochondrial disease) whilst positive is limited. Mitochondrial disease in this context is defined as genetic disease causing an impairment in mitochondrial oxidative phosphorylation (OXPHOS). There are no treatment trials achieving the highest Level I evidence designation. Reasons for this include the relative rarity of mitochondrial disease, the heterogeneity of mitochondrial disease, the natural cofactor status and easy ‘over the counter availability’ of CoQ10 all of which make funding for the necessary large blinded clinical trials unlikely. At this time the best evidence for efficacy comes from controlled trials in common cardiovascular and neurodegenerative diseases with mitochondrial and OXPHOS dysfunction the etiology of which is most likely multifactorial with environmental factors playing on a background of genetic predisposition. There remain questions about dosing, bioavailability, tissue penetration and intracellular distribution of orally administered CoQ10, a compound which is endogenously produced within the mitochondria of all cells. In some mitochondrial diseases and other commoner disorders such as cardiac disease and Parkinson’s disease low mitochondrial or tissue levels of CoQ10 have been demonstrated providing an obvious rationale for supplementation. This paper discusses the current state of the evidence supporting the use of CoQ10 in mitochondrial disease.

J Inherit Metab Dis. 2006 Aug;29(4):589. Epub 2006 Jun 19.
Dietary intervention and oxidative phosphorylation capacity.
Morava E, Rodenburg R, van Essen HZ, De Vries M, Smeitink J.
Secondary deterioration of mitochondrial function has been reported in patients with anorexia and cancer-related malnutrition. Inadequate nutrition, failure to thrive and feeding problems are also common symptoms in children with primary oxidative phosphorylation defects. As a standard intervention protocol we advise an age-appropriate diet and energy intake in our patients diagnosed with a mitochondrial dysfunction. By comparing the results of the first and the second samples from a group of children who underwent repeated muscle biopsies, we observed biochemical improvement in the mitochondrial function in 7 out of 10 patients following dietary advice and intervention. We suggest evaluating the nutritional state by interpretation of the skeletal muscle biochemistry in patients with a suspected oxidative phosphorylation defect. Since an insufficient dietary intake could play a role in secondary mitochondrial dysfunction, nutritional intervention should be performed prior to the biopsy. On the other hand, our data suggest that optimizing the nutritional and energy intake might also improve the utilization of the residual mitochondrial energy-generating capacity in patients with primary oxidative phosphorylation defects.

Ageing Res Rev. 2010 Jan;9(1):20-40. doi: 10.1016/j.arr.2009.09.006. Epub 2009 Oct 1.
Compromised respiratory adaptation and thermoregulation in aging and age-related diseases.
Chan SL, Wei Z, Chigurupati S, Tu W.
Mitochondrial dysfunction and reactive oxygen species (ROS) production are at the heart of the aging process and are thought to underpin age-related diseases. Mitochondria are not only the primary energy-generating system but also the dominant cellular source of metabolically derived ROS. Recent studies unravel the existence of mechanisms that serve to modulate the balance between energy metabolism and ROS production. Among these is the regulation of proton conductance across the inner mitochondrial membrane that affects the efficiency of respiration and heat production. The field of mitochondrial respiration research has provided important insight into the role of altered energy balance in obesity and diabetes. The notion that respiration and oxidative capacity are mechanistically linked is making significant headway into the field of aging and age-related diseases. Here we review the regulation of cellular energy and ROS balance in biological systems and survey some of the recent relevant studies that suggest that respiratory adaptation and thermodynamics are important in aging and age-related diseases.

Nutr Rev. 2011 Feb;69(2):65-75. doi: 10.1111/j.1753-4887.2010.00363.x. Epub 2011 Jan 14.
Mitochondrial response to controlled nutrition in health and disease.
Schiff M, Bénit P, Coulibaly A, Loublier S, El-Khoury R, Rustin P.
Mitochondria exert crucial physiological functions that create complex links among nutrition, health, and disease. While mitochondrial dysfunction with subsequent impairment of oxidative phosphorylation (OXPHOS) is the hallmark of the rare inherited OXPHOS diseases, OXPHOS dysfunction also plays a central role in the pathophysiology of common conditions such as type 2 diabetes and various neurodegenerative disorders. Dietary interventions, especially calorie restriction, have been shown to improve the course of these diseases and to extend the lifespan. Few data are available on the impact of nutraceuticals (macronutrients, vitamins, and cofactors) on primary inherited OXPHOS diseases. This review presents recent knowledge about the impact of nutritional modulation on mitochondria and lifespan regulation and about the development of potential treatments for mitochondrial dysfunction diseases.

Mol Genet Metab. 2003 Sep-Oct;80(1-2):11-26.
The contribution of mitochondria to common disorders.
Enns GM.
Mitochondrial dysfunction secondary to mitochondrial and nuclear DNA mutations has been associated with energy deficiency in multiple organ systems and a variety of severe, often fatal, clinical syndromes. Although the production of energy is indeed the primary function of mitochondria, attention has also been directed toward their role producing reactive oxygen and nitrogen species and the subsequent widespread deleterious effects of these intermediates. The generation of toxic reactive intermediates has been implicated in a number of relatively common disorders, including neurodegenerative diseases, diabetes, and cancer. Understanding the role mitochondrial dysfunction plays in the pathogenesis of common disorders has provided unique insights into a number of diseases and offers hope for potential new therapies.

Semin Cell Dev Biol. 2001 Dec;12(6):449-57.
Reactive oxygen species and mitochondrial diseases.
Kirkinezos IG, Moraes CT.
A variety of diseases have been associated with excessive reactive oxygen species (ROS), which are produced mostly in the mitochondria as byproducts of normal cell respiration. The interrelationship between ROS and mitochondria suggests shared pathogenic mechanisms in mitochondrial and ROS-related diseases. Defects in oxidative phosphorylation can increase ROS production, whereas ROS-mediated damage to biomolecules can have direct effects on the components of the electron transport system. Here, we review the molecular mechanisms of ROS production and damage, as well as the existing evidence of mitochondrial ROS involvement in human diseases.

J Bioenerg Biomembr. 2004 Aug;36(4):381-6.
Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q10 as a potential treatment.
Beal MF.
There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer’s and Parkinson’s diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer’s disease. I also discuss the increasing evidence that Parkinson’s disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson’s and Alzheimer’s diseases.

Amino Acids. 2011 May;40(5):1297-303. doi: 10.1007/s00726-011-0850-1. Epub 2011 Mar 10.
Creatine in mouse models of neurodegeneration and aging.
Klopstock T, Elstner M, Bender A.
The supplementation of creatine has shown a marked neuroprotective effect in mouse models of neurodegenerative diseases (Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis). This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic and anti-oxidant properties of creatine. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral creatine supplementation on aging in 162 aged wild-type C57Bl/6J mice. The median healthy life span of creatine-fed mice was 9% higher than in their control littermates, and they performed significantly better in neurobehavioral tests. In brains of creatine-treated mice, there was a trend toward a reduction of reactive oxygen species and significantly lower accumulation of the “aging pigment” lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data showed that creatine improves health and longevity in mice. Creatine may, therefore, be a promising food supplement to promote healthy human aging. However, the strong neuroprotective effects in animal studies of creatine have not been reproduced in human clinical trials (that have been conducted in Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis). The reasons for this translational gap are discussed. One obvious cause seems to be that all previous human studies may have been underpowered. Large phase III trials over long time periods are currently being conducted for Parkinson’s disease and Huntington’s disease, and will possibly solve this issue.

Ann N Y Acad Sci. 2003 Jun;991:120-31.
Mitochondria, oxidative damage, and inflammation in Parkinson’s disease.
Beal MF.
The pathogenesis of Parkinson’s disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD.

Curr Med Chem. 2003 Oct;10(19):1917-21.
Coenzyme Q10 in neurodegenerative diseases.
Shults CW.
Coenzyme Q(10) (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and/or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease and Friedreich’s ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q(10) can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q(10) can slow the functional decline in these disorders, particularly Parkinson’s disease.

Sci Aging Knowledge Environ. 2002 Oct 16;2002(41):pe16.
Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease.
Ogawa O, Zhu X, Perry G, Smith MA.
An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10′), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD.

J Alzheimers Dis. 2009;17(4):737-51. doi: 10.3233/JAD-2009-1095.
The neurodegenerative mitochondriopathies.
Swerdlow RH.
Mitochondria are physically or functionally altered in many neurodegenerative diseases. This is the case for very rare neurodegenerative disorders as well as extremely common age-related ones such as Alzheimer’s disease and Parkinson’s disease. In some disorders very specific patterns of altered mitochondrial function or systemic mitochondrial dysfunction are demonstrable. Some disorders arise from mitochondrial DNA mutation, some from nuclear gene mutation, and for some the etiology is not definitively known. This review classifies neurodegenerative diseases using mitochondrial dysfunction as a unifying feature, and in doing so defines a group of disorders called the neurodegenerative mitochondriopathies. It discusses what mitochondrial abnormalities have been identified in various neurodegenerative diseases, what is currently known about the mitochondria-neurodegeneration nexus, and speculates on the significance of mitochondrial function in some disorders not classically thought of as mitochondriopathies.

Am J Nephrol. 2007;27(6):545-53. Epub 2007 Aug 30.
From mitochondria to disease: role of the renin-angiotensin system.
de Cavanagh EM, Inserra F, Ferder M, Ferder L.
Mitochondria are energy-producing organelles that conduct other key cellular tasks. Thus, mitochondrial damage may impair various aspects of tissue functioning. Mitochondria generate oxygen- and nitrogen-derived oxidants, being themselves major oxidation targets. Dysfunctional mitochondria seem to contribute to the pathophysiology of hypertension, cardiac failure, the metabolic syndrome, obesity, diabetes mellitus, renal disease, atherosclerosis, and aging. Mitochondrial proteins and metabolic intermediates participate in various cellular processes, apart from their well-known roles in energy metabolism. This emphasizes the participation of dysfunctional mitochondria in disease, notwithstanding that most evidences supporting this concept come from animal and cultured-cell studies. Mitochondrial oxidant production is altered by several factors related to vascular pathophysiology. Among these, angiotensin-II stimulates mitochondrial oxidant release leading to energy metabolism depression. By lowering mitochondrial oxidant production, angiotensin-II inhibition enhances energy production and protects mitochondrial structure. This seems to be one of the mechanisms underlying the benefits of angiotensin-II inhibition in hypertension, diabetes, and aging rodent models. If some of these findings can be reproduced in humans, they would provide a new perspective on the implications that RAS-blockade can offer as a therapeutic strategy. This review intends to present available information pointing to mitochondria as targets for therapeutic Ang-II blockade in human renal and CV disease.

Exp Gerontol. 2008 Oct;43(10):919-28. doi: 10.1016/j.exger.2008.08.007. Epub 2008 Aug 15.
Renin-angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression.
de Cavanagh EM, Flores I, Ferder M, Inserra F, Ferder L.
Chronic renin-angiotensin system inhibition protects against liver fibrosis, ameliorates age-associated mitochondrial dysfunction and increases rodent lifespan. We hypothesized that life-long angiotensin-II-mediated stimulation of oxidant generation might participate in mitochondrial DNA “common deletion” formation, and the resulting impairment of bioenergetic capacity. Enalapril (10 mg/kg/d) or losartan (30 mg/kg/d) administered during 16.5 months were unable to prevent the age-dependent accumulation of rat liver mitochondrial DNA “common deletion”, but attenuated the decrease of mitochondrial DNA content. This evidence – together with the enhancement of NRF-1 and PGC-1 mRNA contents – seems to explain why enalapril and losartan improved mitochondrial functioning and lowered oxidant production, since both the absolute number of mtDNA molecules and increased NRF-1 and PGC-1 transcription are positively related to mitochondrial respiratory capacity, and PGC-1 protects against increases in ROS production and damage. Oxidative stress evoked by abnormal respiratory function contributes to the pathophysiology of mitochondrial disease and human aging. If the present mitochondrial actions of renin-angiotensin system inhibitors are confirmed in humans they may modify the therapeutic significance of that strategy.

Hum Mol Genet. 2008 May 15;17(10):1418-26. doi: 10.1093/hmg/ddn030. Epub 2008 Feb 1.
Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration.
Dufour E, Terzioglu M, Sterky FH, Sörensen L, Galter D, Olson L, Wilbertz J, Larsson NG.
Heteroplasmic mitochondrial DNA (mtDNA) mutations (mutations present only in a subset of cellular mtDNA copies) arise de novo during the normal ageing process or may be maternally inherited in pedigrees with mitochondrial disease syndromes. A pathogenic mtDNA mutation causes respiratory chain deficiency only if the fraction of mutated mtDNA exceeds a certain threshold level. These mutations often undergo apparently random mitotic segregation and the levels of normal and mutated mtDNA can vary considerably between cells of the same tissue. In human ageing, segregation of somatic mtDNA mutations leads to mosaic respiratory chain deficiency in a variety of tissues, such as brain, heart and skeletal muscle. A similar pattern of mutation segregation with mosaic respiratory chain deficiency is seen in patients with mitochondrial disease syndromes caused by inherited pathogenic mtDNA mutations. We have experimentally addressed the role of mosaic respiratory chain deficiency in ageing and mitochondrial disease by creating mouse chimeras with a mixture of normal and respiratory chain-deficient neurons in cerebral cortex. We report here that a low proportion (>20%) of respiratory chain-deficient neurons in the forebrain are sufficient to cause symptoms, whereas premature death of the animal occurs only if the proportion is high (>60-80%). The presence of neurons with normal respiratory chain function does not only prevent mortality but also delays the age at which onset of disease symptoms occur. Unexpectedly, respiratory chain-deficient neurons have adverse effect on normal adjacent neurons and induce trans-neuronal degeneration. In summary, our study defines the minimal threshold level of respiratory chain-deficient neurons needed to cause symptoms and also demonstrate that neurons with normal respiratory chain function ameliorate disease progression. Finally, we show that respiratory chain-deficient neurons induce death of normal neurons by a trans-neuronal degeneration mechanism. These findings provide novel insights into the pathogenesis of mosaic respiratory chain deficiency in ageing and mitochondrial disease.

J Neurosci. 2004 Jun 30;24(26):5909-12.
Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice.
Zhu S1, Li M, Figueroa BE, Liu A, Stavrovskaya IG, Pasinelli P, Beal MF, Brown RH Jr, Kristal BS, Ferrante RJ, Friedlander RM.
Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue sparing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.

Lancet. 2002 Oct 26;360(9342):1323-5.
Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?
Chinnery PF, Samuels DC, Elson J, Turnbull DM.
In man, cells accumulate somatic mutations of mitochondrial DNA (mtDNA) as part of normal ageing. Although the overall concentration of mutant mtDNA is low in tissue as a whole, very high numbers of various mtDNA mutations develop in individual cells within the same person, which causes age-associated mitochondrial dysfunction. Some tumours contain high numbers of mtDNA mutations that are not present in healthy tissues from the same individual. The proportion of mutant mtDNA also rises in patients with progressive neurological disease due to inherited mtDNA mutations. This increase parallels the relentless clinical progression seen in these disorders. Mathematical models suggest that the same basic cellular mechanisms are responsible for the amplification of mutant mtDNA in ageing, in tumours, and in mtDNA disease. The accumulation of cells that contain high levels of mutant mtDNA may be an inevitable result of the normal mechanisms that maintain cellular concentrations of mtDNA.

Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1745-50. Epub 2006 Dec 21.
Cerebral energetic effects of creatine supplementation in humans.
Pan JW, Takahashi K.
There has been considerable interest in the use of creatine (Cr) supplementation to treat neurological disorders. However, in contrast to muscle physiology, there are relatively few studies of creatine supplementation in the brain. In this report, we use high-field MR (31)P and (1)H spectroscopic imaging of human brain with a 7-day protocol of oral Cr supplementation to examine its effects on cerebral energetics (phosphocreatine, PCr; ATP) and mitochondrial metabolism (N-acetyl aspartate, NAA; and Cr). We find an increased ratio of PCr/ATP (day 0, 0.80 +/- 0.10; day 7, 0.85 +/- 09), with this change largely due to decreased ATP, from 2.7 +/- 0.3 mM to 2.5 +/- 0.3 mM. The ratio of NAA/Cr also decreased (day 0, 1.32 +/- 0.17; day 7 1.18 +/- 0.13), primarily from increased Cr (9.6 +/- 1.9 to 10.1 +/- 2.0 mM). The Cr-induced changes significantly correlated with the basal state, with the fractional increase in PCr/ATP negatively correlating with the basal PCr/ATP value (R = -0.74, P < 0.001). As NAA is a measure of mitochondrial function, there was also a significant negative correlation between basal NAA concentrations with the fractional change in PCr and ATP. Thus healthy human brain energetics is malleable and shifts with 7 days of Cr supplementation, with the regions of initially low PCr showing the largest increments in PCr. Overall, Cr supplementation appears to improve high-energy phosphate turnover in healthy brain and can result in either a decrease or an increase in high-energy phosphate concentrations.

Rev Prat. 1993 Apr 1;43(7):868-74.
[Mitochondrial diseases].
[Article in French]
Serratrice G.
Mitochondrial diseases are very complex. Their description, recent but still in progress, makes all classifications risky. In the first part of this article we present the original character of mitochondria, which is due to their functional structure aimed to produce energy, the respiratory chain being fundamental for the phosphorylation/oxidation and ATP production processes. Beside Mendelian transmission, mitochondria have their own DNA which codes for proteins that are few but play an essential role; the nuclear DNA probably has a regulatory effect. For these reasons, explorations of mitochondrial functioning, mainly by morphological, biochemical and genetic techniques, are specific. In the second, clinical part, we analyse the whole range of symptoms and syndromes which includes purely muscular lesions, predominantly nervous lesions and multisystemic lesions. Some syndromes can be individualized on a biochemical basis, whereas other are individualized on a genetic basis involving mainly mutations of mitochondrial DNA. Finally, we merely list lesions the origin of which might be mitochondrial but remains unknown.

Int J Biochem Cell Biol. 2009 Oct;41(10):1949-56. doi: 10.1016/j.biocel.2009.05.004. Epub 2009 May 14.
Dynamic organization of mitochondria in human heart and in myocardial disease.
Hoppel CL, Tandler B, Fujioka H, Riva A.
Heart mitochondria, which, depending on their location within cardiomyofibers, are classified as either subsarcolemmal or interfibrillar, are the major sources of the high energy compound, adenosine triphosphate. Physiological differences between these two populations are reflected by differences in the morphology of their cristae, with those of subsarcolemmal mitochondria being mostly lamelliform, and those of interfibrillar mitochondria being mostly tubular. What determines the configuration of cristae, not only in cardiac mitochondria but in mitochondria in general, is unclear. The morphology of cardiac mitochondria, as well as their physiology, is responsive to the exigencies posed by a large variety of pathological situations. Giant cardiac mitochondria make an appearance in certain types of cardiomyopathy and as a result of dietary, pharmacological, and toxicological manipulation; such megamitochondria probably arise by a combination of fusion and true growth. Some of these enlarged organelles occasionally contain a membrane-bound deposit of beta-glycogen. Those giant mitochondria induced by experimental treatment usually can be restored to normal dimensions simply by supplying the missing nutrient or by deleting the noxious substance. In some conditions, such as endurance training and ischemia, the mitochondrial matrices become pale. Dense rods or plates are present in the outer compartment of mitochondria under certain conditions. Biochemical alterations in cardiac mitochondria appear to be important in heart failure. In aging, only interfibrillar mitochondria exhibit such changes, with the subsarcolemmal mitochondria unaffected. In certain heart afflictions, biochemical defects are not accompanied by obvious morphological transformations. Mitochondria clearly play a cardinal role in homeostasis of the heart.

Endocr Rev. 2010 Jun;31(3):364-95. doi: 10.1210/er.2009-0027. Epub 2010 Feb 15.
The role of mitochondria in the pathogenesis of type 2 diabetes.
Patti ME, Corvera S.
The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.

Nat Rev Drug Discov. 2010 Jun;9(6):465-82. doi: 10.1038/nrd3138.
Cellular bioenergetics as a target for obesity therapy.
Tseng YH, Cypess AM, Kahn CR.
Obesity develops when energy intake exceeds energy expenditure. Although most current obesity therapies are focused on reducing caloric intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis – the physiological process whereby energy is dissipated in mitochondria of brown fat and skeletal muscle in the form of heat in response to external stimuli. There have been significant recent advances in identifying the factors that control the development and function of these tissues, and in techniques to measure brown fat in human adults. In this article, we integrate these developments in relation to the classical understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure.

PLoS One. 2012;7(2):e30554.
Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration
Just Genius, Johanna Geiger, Andreas Bender, Hans-Jürgen Möller, Thomas Klopstock, Dan Rujescu
Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.

Curr Pharm Biotechnol. 2009 Nov;10(7):683-90.
Clinical applications of creatine supplementation on paediatrics.
Evangeliou A1, Vasilaki K, Karagianni P, Nikolaidis N.
Creatine plays a central role in energy metabolism and is synthesized in the liver, kidney and pancreas. In healthy patients, it is transported via the blood stream to the muscles, heart and brain with high and fluctuating energy demands by the molecule creatine transporter. Creatine, although naturally synthesized in the human body, can be ingested in the form of supplements and is commonly used by athletes. The purpose of this review was to assess the clinical applications of creatine supplementation on paediatrics. Creatine metabolism disorders have so far been described at the level of two synthetic steps, guanidinoacetate N-methyltransferase (GAMT) and arginine: glycine amidinotransferase (AGAT), and at the level of the creatine transporter 1(CrT1). GAMT and AGAT deficiency respond positively to substitutive treatment with creatine monohydrate whereas in CrT1 defect, it is not able to replenish creatine in the brain with oral creatine supplementation. There are also data concerning the short and long-term therapeutic benefit of creatine supplementation in children and adults with gyrate atrophy (a result of the inborn error of metabolism with ornithine delta- aminotransferase activity), muscular dystrophy (facioscapulohumeral dystrophy, Becker dystrophy, Duchenne dystrophy and sarcoglycan deficient limb girdle muscular dystrophy), McArdle’s disease, Huntington’s disease and mitochondria-related diseases. Hypoxia and energy related brain pathologies (brain trauma, cerebral ischemia, prematurity) might benefit from Cr supplementation. This review covers also the basics of creatine metabolism and proposed mechanisms of action.

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