Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Abstract

Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. While effective medical interventions are available for some kinds of heart failure, one age-related impairment, diastolic dysfunction in Heart Failure with Preserved Ejection Fraction (HFpEF) is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, we identified ANT1 as mediating the increased proton permeability of old cardiomyocytes. Most importantly, the tetra-peptide drug SS-31 (elamipretide) prevents age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome. Our results uncover a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 is able to reverse this clinically important complication of cardiac aging.