Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Ying Ann Chiao, Huiliang Zhang, Mariya Sweetwyne, Jeremy Whitson, Ying Sonia Ting, Nathan Basisty, Lindsay K. Pino, Ellen Quarles, Ngoc Han Nguyen, Matthew D. Campbell, Tong Zhang, Matthew J. Gaffrey, Gennifer Merrihew, Lu Wang, Yongping Yue, Dongsheng Duan, Henk L. Granzier, Hazel H. Szeto, Wei Jun Qian, David MarcinekMichael J. Maccoss, Peter Rabinovitch

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.

Original languageEnglish (US)
Article numbere55513
Pages (from-to)1-26
Number of pages26
JournaleLife
Volume9
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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