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

Ying Ann Chiao,Dongsheng Duan,Ellen Quarles,Lu Wang,Huiliang Zhang,Tong Zhang,Nathan Basisty,Yongping Yue,Jeremy Whitson,Henk Granzier ,Mariya T Sweetwyne ,Gennifer E Merrihew ,Michael J Maccoss ,David J Marcinek ,Lindsay K Pino ,Matthew D Campbell ,Wei Qian ,Ngoc Hân Nguyen ,Hazel H Szeto ,Matthew J Gaffrey ,Ying S Ting ,Peter S Rabinovitch

doi:10.7554/elife.55513

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.

Highlights

Mitochondrial dysfunction is one of the hallmarks of aging (Lopez-Otın et al, 2013)
The main findings of the study are: 1) enhancing mitochondrial function at late-life by administration of mitochondrial-targeted SS-31 peptide or AAV-mediated expression of mitochondrial targeted catalase can reverse pre-existing cardiac dysfunction in old mice; 2) SS-31 treatment normalizes the age-related increase in mitochondrial proton leak, reduces reactive oxygen species (ROS) production by old cardiomyocytes, and reduces protein oxidative modifications; 3) the rescue of diastolic function by SS-31 in old mice is due, at least in part, to reversal of hypo-phosphorylation of myofilament protein cardiac myosin binding protein C (cMyBP-C); and 4) SS-31 treatment and mitochondrial-targeted catalase (mCAT) expression, while similar in many ways, differentially regulate myofilament protein phosphorylation
These findings are summarized in a proposed mechanistic model of how SS-31 treatment and mCAT expression improve mitochondrial function and regulates myofilament properties to improve cardiomyocytes relaxation and reversing age-related cardiac dysfunction (Figure 8)

Summary

Introduction

Mitochondrial dysfunction is one of the hallmarks of aging (Lopez-Otın et al, 2013). While mitochondria generate the bulk of cellular ATP, they are the major source of reactive oxygen species (ROS) in most cells. SS-31 treatment was previously shown to reduce mitochondrial oxidative damage and prevent pressure overload-induced cardiac hypertrophy and failure in a manner that was highly similar to mCAT (Dai et al, 2011b; Dai et al, 2013; Dai et al, 2012) While these and other studies have shown that combating mitochondrial ROS during the course of a lifetime or during work and pressure overload stress can prevent mitochondrial dysfunction and attenuate cardiac functional decline (Dai et al, 2014a; Dai et al, 2017), it has not been established whether delivering such interventions in later life can rescue pre-existing mitochondrial and cardiac dysfunction. We demonstrate that mitochondrial-targeted interventions can improve mitochondrial function and reverse pre-existing cardiac dysfunction in old mice

Results

Discussion

Findings

Materials and methods