Biological Consequences of Reduced Energy Flux and Inefficient Energy Generation

Alterations in the mitochondrial phospholipid underlie changes in mitochondrial efficiency that precede diabetes and liver and heart disease.

Energy transfer processes are never perfectly efficient. Funai and colleagues have discovered that the degree of inefficiency in cellular energy exchange, particularly during oxidative phosphorylation, has important biological implications. They found that decreased mitochondrial energy flux, such as that occurring with obesity or sedentary behavior, remodels the lipid composition of the mitochondrial inner membrane. Such aberrant changes are sufficient to decrease the efficiency of oxidative phosphorylation and promote respiratory failure in diaphragm muscle, fibrosis in the liver, hypertrophic cardiomyopathy in the heart, and defective thermogenesis in the adipose tissues. These studies suggest potential therapies for improving tissue energetics to treat diabetes and heart disease.


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Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. Park H, He A, Tan M, Johnson JM, Dean JM, Pietka TA, Chen Y, Zhang X, Hsu FF, Razani B, Funai K, Lodhi IJ. J Clin Invest. 2019 Feb 1;129(2):694.

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Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency. Verkerke ARP, Ferrara PJ, Lin C, Johnson JM, Ryan TE, Maschek JA, Eshima H, Paran CW, Laing BT, Siripoksup P, Tippetts TS, Wentzler EJ, Huang H, Spangenburg EE, Brault JJ, Villanueva CJ, Summers SA, Holland WL, Cox JE, Vance DE, Neufer PD, Funai K. Nature Metabolism. 2019 Sept; 1:876.

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Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity. Heden TD, Johnson JM, Ferrara PJ, Eshima H, Verkerke ARP, Wentzler EJ, Siripoksup P, Narowski TM, Coleman CB, Lin CT, Ryan TE, Reidy PT, de Castro Brás LE, Karner CM, Burant CF, Maschek JA, Cox JE, Mashek DG, Kardon G, Boudina S, Zeczycki TN, Rutter J, Shaikh SR, Vance JE, Drummond MJ, Neufer PD, Funai K. Sci Adv. 2019 Sep;5(9):eaax8352.

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