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Sci Adv. 2019 Sep 11;5(9):eaax8352. doi: 10.1126/sciadv.aax8352. eCollection 2019 Sep.

Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity.

Heden TD1,2,3, Johnson JM1,2,4,5,6, Ferrara PJ1,2,4,5,6, Eshima H4, Verkerke ARP1,2,4,5,6, Wentzler EJ1,2, Siripoksup P4,6, Narowski TM1,2, Coleman CB1,2, Lin CT1,7, Ryan TE1,7,8, Reidy PT4,6, de Castro Brás LE7, Karner CM9, Burant CF10, Maschek JA11, Cox JE4,11,12, Mashek DG3, Kardon G13, Boudina S4,5,14, Zeczycki TN1,15, Rutter J4,12, Shaikh SR1,15,16, Vance JE17, Drummond MJ4,5,6,14, Neufer PD1,2,7, Funai K1,2,4,5,6,7,14.

Author information

1
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA.
2
Department of Kinesiology, East Carolina University, Greenville, NC, USA.
3
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
4
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.
5
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
6
Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, UT, USA.
7
Department of Physiology, East Carolina University, Greenville, NC, USA.
8
Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, USA.
9
Department of Orthopedic Surgery & Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
10
Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA.
11
Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT, USA.
12
Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
13
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
14
Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
15
Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC, USA.
16
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
17
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Abstract

Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle-specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.

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