Mitochondrial Proton Leak Implicated in Cardiovascular Dysfunction Leading to Heart Failure

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Researchers here use the mitochondrially targeted peptide SS-31 to demonstrate a role for increased proton leak and consequent mitochondrial dysfunction in the progression of cardiomyopathy towards heart failure. Mitochondria are the power plants of the cell, producing chemical energy store molecules to power cellular processes. With age, mitochondria become less functional throughout the body. This is particularly problematic in energy-hungry tissues such as heart muscle. Numerous lines of research and development attempt to fix one or another of the many proximate causes of that loss of mitochondrial function, with varying degrees of success. Here, it is noted that SS-31 can restore a third of the lost diastolic function in old mice by reducing proton leak and improving mitochondrial performance.

While more attention has been placed on mitochondrial electron leak and consequent free radical generation, proton leak is a highly significant aspect of mitochondrial energetics, as it accounts for more than 20% of oxygen consumption in the liver and 35-50% of that in muscle in the resting state. There are two types of proton leak in the mitochondria: (1) constitutive, basal proton leak, and (2) inducible, regulated proton leak, including that mediated by uncoupling proteins (UCPs). In skeletal muscle, a majority of basal proton conductance has been attributed to adenine nucleotide translocase (ANT). Although aging-related increased mitochondrial proton leak was detected in the mouse heart, kidneys, and liver by indirect measurement of oxygen consumption in isolated mitochondria, direct evidence of functional impact remains to be further investigated. Moreover, the exact site and underlying mechanisms responsible for aging-related mitochondrial proton leak are unclear.

SS-31 (elamipretide) binds to cardiolipin-containing membranes and improves cristae curvature. Prevention of cytochrome c peroxidase activity and release has been proposed as its major basis of activity. SS-31 is highly effective in increasing resistance to a broad range of diseases, including heart ischemia reperfusion injury, heart failure, neurodegenerative disease, and metabolic syndrome. In aged mice, SS-31 ameliorates kidney glomerulopathy and brain oxidative stress and has shown beneficial effects on skeletal muscle performance. We have recently shown that administration of SS-31 to 24-month-old mice for 8 weeks reverses the age-related decline in diastolic function, restoring this parameter 35% toward that of young (5-month-old) mice. However, how SS-31 benefits and protects aged cardiac cells remains unclear.

In this report, we investigated the effect and underlying mechanism of action of SS-31 on aged cardiomyocytes, especially on the mitochondrial proton leak. Using the naturally aged rodent model we provided direct evidence of increased proton leak as the primary energetic change in aged mitochondria. We further show that the inner membrane protein ANT1 mediates the augmented proton entry in the old mitochondria. Most significantly, we demonstrate that SS-31 acutely prevents the excessive mitochondrial proton entry and rejuvenates mitochondrial function through direct association with ANT1 and stabilization of the ATP synthasome.

Link: https://doi.org/10.7554/eLife.60827

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source https://www.fightaging.org/archives/2020/12/mitochondrial-proton-leak-implicated-in-cardiovascular-dysfunction-leading-to-heart-failure/