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

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.