title: Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging.
abstract: Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a cascade of biological processes including aging. A number of autophagy regulators have been identified. Here we demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with the most common single point mutation in humans, governs cardiac aging through regulation of autophagy. Myocardial mechanical and autophagy properties were examined in young (4months) and old (26-28months) wild-type (WT) and global ALDH2 transgenic mice. ALDH2 overexpression shortened lifespan by 7.7% without affecting aging-associated changes in plasma metabolic profiles. Myocardial function was compromised with aging associated with cardiac hypertrophy, the effects were accentuated by ALDH2. Aging overtly suppressed autophagy and compromised autophagy flux, the effects were exacerbated by ALDH2. Aging dampened phosphorylation of JNK, Bcl-2, IKKβ, AMPK and TSC2 while promoting phosphorylation of mTOR, the effects of which were exaggerated by ALDH2. Co-immunoprecipitation revealed increased dissociation between Bcl-2 and Beclin-1 (result of decreased Bcl-2 phosphorylation) in aging, the effect of which was exacerbated with ALDH2. Chronic treatment of the autophagy inducer rapamycin alleviated aging-induced cardiac dysfunction in both WT and ALDH2 mice. Moreover, activation of JNK and inhibition of either Bcl-2 or IKKβ overtly attenuated ALDH2 activation-induced accentuation of cardiomyocyte aging. Examination of the otherwise elderly individuals revealed a positive correlation between cardiac function/geometry and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may suppress myocardial autophagy possibly through a complex JNK-Bcl-2 and IKKβ-AMPK-dependent mechanism en route to accentuation of myocardial remodeling and contractile dysfunction in aging. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.affiliation: University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Lindsay K
authors.initials: LK
authors.lastname: Hueckstaedt
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China. Electronic address: ge.junbo@zs-hospital.sh.cn.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address: jren@uwyo.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: ALDH2; Aging; Autophagy; Bcl-2; Cardiomyocyte; IKKβ; JNK