Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity

Timothy D. Heden, Jordan M. Johnson, Patrick J. Ferrara, Hiroaki Eshima, Anthony R.P. Verkerke, Edward J. Wentzler, Piyarat Siripoksup, Tara M. Narowski, Chanel B. Coleman, Chien Te Lin, Terence E. Ryan, Paul T. Reidy, Lisandra E. de Castro Brás, Courtney M. Karner, Charles F. Burant, J. Alan Maschek, James E. Cox, Douglas G. Mashek, Gabrielle Kardon, Sihem BoudinaTonya N. Zeczycki, Jared Rutter, Saame Raza Shaikh, Jean E. Vance, Micah J. Drummond, P. Darrell Neufer, Katsuhiko Funai

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Article numbereaax8352
JournalScience Advances
Issue number9
StatePublished - Sep 11 2019

Bibliographical note

Funding Information:
This work was supported by NIH grants DK107397, DK109888, DK095774, and AG063077 to K.F.; DK110656 to P.D.N.; AG050781 to M.J.D.; HL123647 and AT008375 to S.R.S.; AR071967 to C.M.K.; HL129632 to T.E.R.; DK099034 and DK097153 to C.F.B.; and DK109556 and DK110338 to T.D.H. This work was also supported by P&F Funding from P30 DK020579 at Washington University in St. Louis to K.F.; Larry H. & Gail Miller Foundation grant to P.J.F.; Uehara Memorial Foundation to H.E.; and American Heart Association grants 19PRE34380991 to J.M.J., 18PRE33960491 to A.R.P.V., and 16POST30980047 and 19POST343701052 to T.D.H. University of Utah Metabolomics Core Facility was supported by S10 OD016232, S10 OD021505, and U54 DK110858.


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