SIRT3 deficiency exacerbates p53/Parkin‑mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts

Li,Yan; Ma,Ying; Song,Liqiang; Yu,Lu; Zhang,Le; Zhang,Yingmei; Xing,Yuan; Yin,Yue; Ma,Heng

doi:10.3892/ijmm.2018.3555

SIRT3 deficiency exacerbates p53/Parkin‑mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts

Authors:
- Yan Li
- Ying Ma
- Liqiang Song
- Lu Yu
- Le Zhang
- Yingmei Zhang
- Yuan Xing
- Yue Yin
- Heng Ma
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Affiliations: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Respirology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Pathology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Physiology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: March 9, 2018 https://doi.org/10.3892/ijmm.2018.3555
Pages: 3517-3526

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Abstract

Mitochondrial dynamics have critical roles in aging, and their impairment represents a prominent risk factor for myocardial dysfunction. Mitochondrial deacetylase sirtuin (SIRT)3 contributes greatly to the prevention of redox stress and cell aging. The present study explored the role of SIRT3 on myocardium aging. Western blot analysis demonstrated that SIRT3 expression levels were significantly lower in the myocardia of aged mice compared with young mice. Immunoprecipitation and western blot assays indicated that the activity of mitochondrial manganese superoxide dismutase (MnSOD) and peroxisome proliferator‑activated receptor γ coactivator (PGC)‑1α was reduced in the aged heart. To further explore the association between SIRT3 and myocardial senescence, SIRT3 heart‑specific knockout (SIRT3-/-) mice were used in the present study. The results revealed that obvious features of aging were present in the myocardium of SIRT3-/- mice, including mitochondrial protein dysfunction, enhanced oxidative stress, and energy metabolism dysfunction. SIRT3 deficiency impaired Parkin‑mediated mitophagy by increasing p53‑Parkin binding and blocking the mitochondrial translocation of Parkin in cardiomyocytes. Injection of autophagy agonist CCCP significantly increased the mitochondrial Parkin level in young wild‑type hearts but not in aged hearts; the effect was less pronounced in SIRT3-/- hearts. These data suggest that CCCP‑induced Parkin translocation was reduced in aged and SIRT3-/- hearts. CCCP‑induced mitochondrial clearance, which could be rescued by autophagy antagonist bafilomycin‑A1, was markedly weakened in aged and SIRT3-/- hearts vs. young hearts. SIRT3 deficiency exacerbated p53/Parkin‑mediated mitophagy inhibition and disrupted mitochondrial homeostasis, suggesting that loss of SIRT3 may increase the susceptibility of aged hearts to cardiac dysfunction. Therapeutic activation of SIRT3 and improved mitochondrial function may ameliorate the symptoms of cardiac aging.

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