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.
Int J Mol Med. 2018 Jun;41(6):3517-3526. doi: 10.3892/ijmm.2018.3555. Epub 2018 Mar 9.
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.
线粒体动力学在衰老过程中起着关键作用，其功能障碍是心肌功能障碍的一个突出危险因素。线粒体去乙酰化酶 SIRT3 对预防氧化应激和细胞衰老有重要作用。本研究探讨了 SIRT3 在心衰中的作用。Western blot 分析表明，与年轻小鼠相比，老年小鼠心肌中的 SIRT3 表达水平明显降低。免疫沉淀和 Western blot 分析表明，老年心脏中线粒体锰超氧化物歧化酶（MnSOD）和过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1α的活性降低。为了进一步探讨 SIRT3 与心肌衰老的关系，本研究使用 SIRT3 心脏特异性敲除（SIRT3-/-）小鼠。结果表明，SIRT3-/-小鼠的心肌出现明显的衰老特征，包括线粒体蛋白功能障碍、氧化应激增强和能量代谢功能障碍。SIRT3 缺乏通过增加 p53-Parkin 结合并阻断 Parkin 在心肌细胞中的线粒体易位，损害 Parkin 介导的线粒体自噬。自噬激动剂 CCCP 显著增加了年轻野生型心脏中线粒体 Parkin 水平，但在老年心脏中没有；SIRT3-/-心脏的效果不明显。这些数据表明，在老年和 SIRT3-/-心脏中，CCCP 诱导的 Parkin 易位减少。自噬拮抗剂巴弗洛霉素 A1 可挽救 CCCP 诱导的线粒体清除，但在老年和 SIRT3-/-心脏中明显减弱。CCCP 诱导的线粒体清除，可被自噬拮抗剂巴弗洛霉素 A1 挽救，但在老年和 SIRT3-/-心脏中明显减弱。SIRT3 缺乏加剧了 p53/Parkin 介导的线粒体自噬抑制，破坏了线粒体的动态平衡，提示 SIRT3 的缺失可能增加老年心脏发生心功能障碍的易感性。SIRT3 的治疗性激活和改善线粒体功能可能改善心脏衰老的症状。
