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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial function can reverse pre-existing age-related diseases is not well-established. Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans, and we show here that 8-week treatment with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit in old mice. Mechanistically, SS-31 treatment normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice; these cellular changes were accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. The improvement in diastolic function was associated with increased phosphorylation at Ser282 of cMyBP-C but was independent of titin isoform shift. SS-31 treatment cannot further improve cardiac function of old mice that express mitochondrial-targeted catalase (mCAT), implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Late-life viral expression of mCAT produced similar functional benefits in old mice, further indicating that reduction of mitochondrial ROS as a critical mechanism. Despite their similar functional benefits, SS-31 and mCAT differentially regulated cMyBP-C and cTnI phosphorylation, suggesting divergence of mechanisms downstream of mitochondrial ROS reduction. Overall, 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 of cardiac aging.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jan 2 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice'. Together they form a unique fingerprint.

Cite this