SIRT3 improved peroxisomes-mitochondria interplay and prevented cardiac hypertrophy via preserving PEX5 expression.
SIRT3 improved peroxisomes-mitochondria interplay and prevented cardiac hypertrophy via preserving PEX5 expression.
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SIRT 3通过保护PEX 5表达改善过氧化物酶体-线粒体相互作用并防止心肌肥大。
DOI：
10.1016/j.redox.2023.102652
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发表时间：
2023-06
期刊：
影响因子：
11.4
通讯作者：
Li, Zhuoming
中科院分区：
文献类型：
--
作者：
Wang, Minghui;Ding, Yanqing;Hu, Yuehuai;Li, Zeyu;Luo, Wenwei;Liu, Peiqing;Li, Zhuoming
本研究确定了Sirtuin 3（SIRT 3）对病理性心脏肥大的保护作用的新机制，超越了其作为线粒体脱乙酰酶的公认作用。SIRT 3通过保持过氧化物酶体生物发生因子5（PEX 5）的表达来调节过氧化物酶体-线粒体相互作用，从而改善线粒体功能。在Sirt 3 −/−小鼠和血管紧张素II诱导的心脏肥大小鼠的心脏以及SIRT 3沉默的心肌细胞中观察到PEX 5的下调。PEX 5敲低可消除SIRT 3对心肌细胞肥大的保护作用，而PEX 5过表达可减轻SIRT 3抑制诱导的肥大反应。PEX 5参与SIRT 3对线粒体稳态的调节，包括线粒体膜电位、线粒体动态平衡、线粒体形态和超微结构以及ATP的产生。此外，SIRT 3通过PEX 5减轻了肥大心肌细胞中的过氧化物酶体异常，如过氧化物酶体生物发生和超微结构的改善以及过氧化物酶体过氧化氢酶的增加和氧化应激的抑制所暗示的。最后，PEX 5作为过氧化物酶体-线粒体相互作用的关键调节剂的作用被证实，因为由PEX 5缺乏引起的过氧化物酶体缺陷导致线粒体损伤。总之，这些观察结果表明，SIRT 3可以通过保持过氧化物酶体-线粒体经由PEX 5的相互作用来维持线粒体稳态。我们的研究结果提供了一个新的理解SIRT 3在心肌细胞线粒体调节通过细胞器间通讯的作用。SIRT 3通过保护PEX 5表达和改善过氧化物酶体-线粒体相互作用来抑制心肌肥大。PEX 5参与SIRT 3对线粒体稳态和过氧化物酶体适应性的调节。PEX 5是心肌细胞中过氧化物酶体-线粒体相互作用的关键调节因子。
The present study identified a novel mechanism underlying the protective effect of Sirtuin 3 (SIRT3) against pathological cardiac hypertrophy, beyond its well-accepted role as a deacetylase in mitochondria. SIRT3 modulates the peroxisomes-mitochondria interplay by preserving the expression of peroxisomal biogenesis factor 5 (PEX5), thereby improving mitochondrial function. Downregulation of PEX5 was observed in the hearts of Sirt3−/− mice and angiotensin II-induced cardiac hypertrophic mice, as well as in cardiomyocytes with SIRT3 silencing. PEX5 knockdown abolished the protective effect of SIRT3 against cardiomyocyte hypertrophy, whereas PEX5 overexpression alleviated the hypertrophic response induced by SIRT3 inhibition. PEX5 was involved in the regulation of SIRT3 in mitochondrial homeostasis, including mitochondrial membrane potential, mitochondrial dynamic balance, mitochondrial morphology and ultrastructure, as well as ATP production. In addition, SIRT3 alleviated peroxisomal abnormalities in hypertrophic cardiomyocytes via PEX5, as implied by improvement of peroxisomal biogenesis and ultrastructure, as well as increase of peroxisomal catalase and repression of oxidative stress. Finally, the role of PEX5 as a key regulator of the peroxisomes-mitochondria interplay was confirmed, since peroxisomal defects caused by PEX5 deficiency led to mitochondrial impairment. Taken together, these observations indicate that SIRT3 could maintain mitochondrial homeostasis by preserving the peroxisomes-mitochondria interplay via PEX5. Our findings provide a new understanding of the role of SIRT3 in mitochondrial regulation via interorganelle communication in cardiomyocytes. SIRT3 inhibited cardiac hypertrophy via preserving PEX5 expression and ameliorating peroxisomes-mitochondria interplay. PEX5 was involved in the regulation of SIRT3 in mitochondrial homeostasis and peroxisomal fitness. PEX5 served as a key regulator for peroxisomes-mitochondria interplay in cardiomyocyte.
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通讯作者：
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