Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy

Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity.Mice challenged with streptozotocin(STZ,200 mg/kg,via intraperitoneal injection)exhibited pathological alterations,including reduced respiratory exchange ratio,dampened fractional shortening and ejection fraction,increased left ventricular end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile anomalies,intracellular Ca2+defects,myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,which were overtly attenuated or accentuated by ALDH2 overexpression or knockout,respectively.Diabetic patients also exhibited reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.In addition,STZ challenge altered expression levels of mitochondrial proteins(PGC-1αand UCP2)and Ca2+regulatory proteins(SERCA,Na+–Ca2+exchanger,and phospholamban),dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3β,and Foxo3a,and elevated PTEN phosphorylation,most of which were reversed or worsened by ALDH2 overexpression or knockout,respectively.Furthermore,the novel ALDH2 activator torezolid,as well as the classical ALDH2 activator Alda-1,protected against STZ-or high glucose-induced in vivo or in vitro cardiac anomalies,which was nullified by inhibition of Akt,GSK3β,Parkin,or mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3βactivation,Parkin mitophagy,and mitochondrial function.