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

Chiao, Ying Ann, Zhang, Huiliang, Sweetwyne, Mariya, Whitson, Jeremy, Ting, Ying Sonia, Basisty, Nathan, Pino, Lindsay K, Quarles, Ellen, Nguyen, Ngoc-Han, Campbell, Matthew, Zhang, Tong, Gaffrey, Matthew J, Merrihew, Gennifer, Wang, Lu, Yue, Yongping, Duan, Dongsheng, Granzier, Henk L, Szeto, Hazel H, Qian, Wei-Jun, Marcinek, David, MacCoss, Michael J and Rabinovitch, Peter (2020) Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. eLife, 9. ISSN 2050-084X

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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.

Item Type: Article
Divisions: Faculty of Health Sciences and Wellbeing
Depositing User: Matthew Campbell
Date Deposited: 05 Feb 2021 10:25
Last Modified: 05 Feb 2021 10:30
ORCID for Matthew Campbell: ORCID iD

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