Role of Hydrogen Sulfide in Mitochondrial Remodeling and Myocardial Energetics

Mitochondrial ATP production efficiency is crucial for normal function, survival and repair after ischemia. Although hydrogen sulfide (H2S) has been known as a cardioprotective agent, its production regulation and its role in myocardial mitochondrial remodeling and energetics during normal and diabetic conditions are unknown. The long-term goal of this proposal is to dissect alterations in the regulatory mechanisms of mitochondrial remodeling and sulfide metabolism leading to changes in the heart energetics and function in the context of cardiomyopathy and ischemia. Interestingly, regulation of myocardial mitochondrial fission/fusion ratio, cristae density, electron transport (aerobic and anaerobic), ATP production (normal & ischemic) efficiency, membrane potential, survivability and oxygen consumption rates are dependent on the H2S levels without apparent changes in the mitochondrial density during diabetes. Importantly, inhibition of Drp1, the key mitochondrial fission promoter, resulted in the ischemic injury recovery concurrent with H2S production enhancement. Furthermore, the rescue of H2S levels restored c-Met levels and signal transduction, concomitant with the rescue of H2S generating enzyme, CSE. Notably, enhancement of c-Met signaling also raised H2S levels, CSE levels and Opa1 levels (the regulator of respiratory supercomplex assembly). The central hypothesis is that H2S level rescue enhances mitochondrial aerobic and anaerobic ATP production through the reversal of adverse mitochondrial remodeling and stimulation of sulfide metabolism involving a mutual feedback regulation loop between c-Met signaling and H2S production. Aim 1: To determine whether the H2S levels increase cristae density, mitochondrial respiratory efficiency and aerobic ATP production. Aim 2: To determine whether the H2S levels modulate anaerobic electron transport and ATP production during ischemia. Aim 3: To determine whether the c-Met signaling restoration is sufficient to rescue the H2S levels, thereby reversing abnormal mitochondrial remodeling and H2S metabolism. We will test the aims in diabetic Akita mice, which have a uniquely lower cristae density and ATP production, in parallel with H2S depletion and c-Met signaling deficiency. The results will aid in the invention of potent drugs for mitochondrial diseases and heart failure.