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

内科学 粒体自噬 线粒体 帕金 生物 品脱1 化学 自噬 细胞生物学 医学 生物化学 醛脱氢酶 细胞凋亡 疾病 帕金森病
作者
Yingmei Zhang,Rongjun Zou,Miyesaier Abudureyimu,Qiong Liu,Jipeng Ma,Haixia Xu,Wei Yu,Jian Yang,Jianguo Jia,Sanli Qian,Haichang Wang,Yang Yang,Xin Wang,Xiaoping Fan,Jun Ren
出处
期刊:Journal of Molecular Cell Biology [Oxford University Press]
卷期号:15 (9) 被引量:5
标识
DOI:10.1093/jmcb/mjad056
摘要

Abstract 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-1α and 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 GSK3β activation, Parkin mitophagy, and mitochondrial function.
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