PUFA Decrease Cellular Energy Production

Also see:
PUFA – Accumulation & Aging
Free Fatty Acids Suppress Cellular Respiration
PUFA Breakdown Products Depress Mitochondrial Respiration
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Randle Cycle
Protective “Essential Fatty Acid Deficiency”
Errors in Nutrition: Essential Fatty Acids
ATP Regulates Cell Water

“With aging, cells have less ability to produce energy, and are often more easily stimulated. The accumulation of polyunsaturated fats is one of the factors that reduce the ability of mitochondria to produce energy (Zhang, et al., 2006, 2009; Yazbeck, et al., 1989). Increased estrogen exposure, decreased thyroid hormone, an increased ratio of iron to copper, and lack of light, are other factors that impair the cytochrome oxidase enzyme.” -Ray Peat, PhD

Comp Biochem Physiol A Comp Physiol. 1989;94(2):273-6.
The effects of essential fatty acid deficiency on brown adipose tissue activity in rats maintained at thermal neutrality.
Yazbeck J, Goubern M, Senault C, Chapey MF, Portet R.
1. The consequences of essential fatty acid (EFA) deficiency on the resting metabolism, food efficiency and brown adipose tissue (BAT) thermogenic activity were examined in rats maintained at thermal neutrality (28 C). 2. Weanling male Long-Evans rats were fed a hypolipidic semi-purified diet (control diet: 2% sunflower oil; EFA-deficient diet: 2% hydrogenated coconut oil) for 9 weeks. 3. They were kept at 28 C for the last 5 weeks. Compared to controls, in EFA-deficient rats the growth shortfall reached 21% at killing. 4. As food intake was the same in EFA-deficient and control rats, food efficiency was thus decreased by 40%. 5. Resting metabolism expressed per surface unit was 15% increased. 6. Non-renal water loss was increased by 88%. 7. BAT weight was 28% decreased but total and mitochondrial proteins were not modified. 8. Heat production capacity, tested by GDP binding per BAT was 69% increased in BAT of deficient rats. 9. The stimulation of BAT was established by two other tests: GDP inhibition of mitochondrial O2 consumption and swelling of mitochondria. 10. It is suggested that the observed enhancement of resting metabolism in EFA-deficient rats is, in part, due to an activation of heat production in BAT.

Am J Physiol Cell Physiol. 2006 May;290(5):C1321-33.
Polyunsaturated fatty acids mobilize intracellular Ca2+ in NT2 human teratocarcinoma cells by causing release of Ca2+ from mitochondria.
Zhang BX, Ma X, Zhang W, Yeh CK, Lin A, Luo J, Sprague EA, Swerdlow RH, Katz MS.
In a variety of disorders, overaccumulation of lipid in nonadipose tissues, including the heart, skeletal muscle, kidney, and liver, is associated with deterioration of normal organ function, and is accompanied by excessive plasma and cellular levels of free fatty acids (FA). Increased concentrations of FA may lead to defects in mitochondrial function found in diverse diseases. One of the most important regulators of mitochondrial function is mitochondrial Ca(2+) ([Ca(2+)](m)), which fluctuates in coordination with intracellular Ca(2+) ([Ca(2+)](i)). Polyunsaturated FA (PUFA) have been shown to cause [Ca(2+)](i) mobilization albeit by unknown mechanisms. We have found that PUFA but not monounsaturated or saturated FA cause [Ca(2+)](i) mobilization in NT2 human teratocarcinoma cells. Unlike the [Ca(2+)](i) response to the muscarinic G protein-coupled receptor agonist carbachol, PUFA-mediated [Ca(2+)](i) mobilization in NT2 cells is independent of phospholipase C and inositol-1,4,5-trisphospate (IP(3)) receptor activation, as well as IP(3)-sensitive internal Ca(2+) stores. Furthermore, PUFA-mediated [Ca(2+)](i) mobilization is inhibited by the mitochondria uncoupler carboxyl cyanide m-chlorophenylhydrozone. Direct measurements of [Ca(2+)](m) with X-rhod-1 and (45)Ca(2+) indicate that PUFA induce Ca(2+) efflux from mitochondria. Further studies show that ruthenium red, an inhibitor of the mitochondrial Ca(2+) uniporter, blocks PUFA-induced Ca(2+) efflux from mitochondria, whereas inhibitors of the mitochondrial permeability transition pore cyclosporin A and bongkrekic acid have no effect. Thus PUFA-gated Ca(2+) release from mitochondria, possibly via the Ca(2+) uniporter, appears to be the underlying mechanism for PUFA-induced [Ca(2+)](i) mobilization in NT2 cells.

PLoS ONE 4(6): e6048. doi:10.1371/journal.pone.0006048
Linoleic Acid-Induced Mitochondrial Ca2+ Efflux Causes Peroxynitrite Generation and Protein Nitrotyrosylation
Hong-Mei Zhang1, Howard Dang2, Chih-Ko Yeh3,4, Bin-Xian Zhang1,4*
It is well known that excessive non-esterified fatty acids in diabetes contribute to the pathogenesis of renal complications although the mechanism remains elusive. Enhanced oxidative stress has been hypothesized as a unified factor contributing to diabetic complications and increased protein nitrotyrosylation has been reported in the kidneys of diabetic patients. In the current manuscript we described that linoleic acid (LA) caused mitochondrial Ca2+ efflux and peroxynitrite production, along with increased nitrotyrosine levels of cellular proteins in primary human mesangial cells. The peroxynitrite production by LA was found to depend on mitochondrial Ca2+ efflux. Downregulation of hsp90β1, which has been previously shown to be essential for polyunsaturated fatty acid-induced mitochondrial Ca2+ efflux, significantly diminished LA-responsive mitochondrial Ca2+ efflux and the coupled peroxynitrite generation, implicating a critical role of hsp90β1 in the LA responses. Our results further demonstrated that mitochondrial complexes I and III were directly involved in the LA-induced peroxynitrite generation. Using the well established type 2 diabetic animal model db/db mice, we observed a dramatically enhanced LA responsive mitochondrial Ca2+ efflux and protein nitrotyrosylation in the kidney. Our study thus demonstrates a cause-effect relationship between LA and peroxynitrite or protein nitrotyrosylation and provides a novel mechanism for lipid-induced nephropathy in diabetes.

Endocrine. 2011 Apr;39(2):128-38. Epub 2010 Dec 15.
Long-term exposure of INS-1 rat insulinoma cells to linoleic acid and glucose in vitro affects cell viability and function through mitochondrial-mediated pathways.
Tuo Y, Wang D, Li S, Chen C.
Obesity with excessive levels of circulating free fatty acids (FFAs) is tightly linked to the incidence of type 2 diabetes. Insulin resistance of peripheral tissues and pancreatic β-cell dysfunction are two major pathological changes in diabetes and both are facilitated by excessive levels of FFAs and/or glucose. To gain insight into the mitochondrial-mediated mechanisms by which long-term exposure of INS-1 cells to excess FFAs causes β-cell dysfunction, the effects of the unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. INS-1 cells were incubated with 0, 50, 250 or 500 μM linoleic acid/0.5% (w/v) BSA for 48 h under culture conditions of normal (11.1 mM) or high (25 mM) glucose in serum-free RPMI-1640 medium. Cell viability, apoptosis, glucose-stimulated insulin secretion, Bcl-2, and Bax gene expression levels, mitochondrial membrane potential and cytochrome c release were examined. Linoleic acid 500 μM significantly suppressed cell viability and induced apoptosis when administered in 11.1 and 25 mM glucose culture medium. Compared with control, linoleic acid 500 μM significantly increased Bax expression in 25 mM glucose culture medium but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane potential (ΔΨm) and significantly promoted cytochrome c release from mitochondria in both 11.1 mM glucose and 25 mM glucose culture medium, further reducing glucose-stimulated insulin secretion, which is dependent on normal mitochondrial function. With the increase in glucose levels in culture medium, INS-1 β-cell insulin secretion function was deteriorated further. The results of this study indicate that chronic exposure to linoleic acid-induced β-cell dysfunction and apoptosis, which involved a mitochondrial-mediated signal pathway, and increased glucose levels enhanced linoleic acid-induced β-cell dysfunction.

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