<br>SIRT3 通过 OPA1 控制的线粒体动力学促进人 iPSC 衍生的心肌细胞的代谢成熟,Free Radical Biology and Medicine

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SIRT3 通过 OPA1 控制的线粒体动力学促进人 iPSC 衍生的心肌细胞的代谢成熟
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2022-12-31 , DOI: 10.1016/j.freeradbiomed.2022.12.101
Rui Wang ₁ , Hao Xu ₂ , Bin Tan ₁ , Qin Yi ₁ , Yanting Sun ₁ , Han Xiang ₁ , Tangtian Chen ₁ , Huiwen Liu ₁ , Qiumin Xie ₁ , Li Wang ₁ , Jie Tian ₃ , Jing Zhu ₁

Affiliation

人诱导多能干细胞衍生的心肌细胞（HiPSC-CM）的代谢模式和能量学远低于正常成人心肌细胞，这限制了它们在疾病治疗和再生医学中的应用。已经证明 SIRT3 是一种线粒体靶向脱乙酰酶，在生理和病理条件下控制线粒体代谢。在这项研究中，我们研究了 SIRT3 在 HiPSC-CMs 能量代谢中的作用和调控机制。我们发现 SIRT3 的表达在 HiPSC-CMs 的分化和成熟过程中增加。敲低 SIRT3 会损害线粒体结构、线粒体呼吸能力和脂肪酸氧化，但增强糖酵解。然而，和厚朴酚是 SIRT3 的药理激活剂，可改善线粒体超微结构和能量学，并促进 HiPSC-CMs 的氧化磷酸化。此外，SIRT3 调节 OPA1 的乙酰化，敲低 OPA1 阻断了和厚朴酚对能量代谢的促进，同时敲低了 OPA1 受损的线粒体融合、线粒体呼吸能力和脂肪酸氧化，这些在 HiPSC-CMs 中被 M1 （一种线粒体融合启动子）逆转。综上所述，SIRT3 通过靶向 HiPSC-CMs 中 OPA1 控制的线粒体动力学来调节能量学并促进代谢重塑，靶向 SIRT3 可能在心血管疾病的治疗和 HiPSC-CMs 在再生医学中的应用具有启示意义。

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SIRT3 promotes metabolic maturation of human iPSC-derived cardiomyocytes via OPA1-controlled mitochondrial dynamics

The metabolic patterns and energetics of human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) are much less than those of normal adult cardiomyocytes, which has limited their application in disease therapy and regenerative medicine. It has been demonstrated that SIRT3, a mitochondria-target deacetylase, controls mitochondrial metabolism in physiological and pathological conditions. In this research, We investigated the role and regulatory mechanism of SIRT3 in energy metabolism in HiPSC-CMs. We found that the expression of SIRT3 was increased during the differentiation and maturation of HiPSC-CMs. Knocking down SIRT3 impaired mitochondrial structure, mitochondrial respiration capacity, and fatty acid oxidation but enhanced glycolysis. However, honokiol, a pharmacological activator of SIRT3, improved the mitochondrial ultrastructure and energetics, and promoted oxidative phosphorylation in HiPSC-CMs. Furthermore, SIRT3 regulated the acetylation of OPA1, and the knockdown of OPA1 blocked the promotion of energy metabolism by honokiol, meanwhile, knocking down OPA1 impaired mitochondrial fusion, mitochondrial respiration capacity, and fatty acid oxidation which were reversed by M1 (a mitochondrial fusion promoter) in HiPSC-CMs. In summary, SIRT3 regulated energetics and promoted metabolism remodeling by targeting the OPA1-controlled mitochondrial dynamics in HiPSC-CMs, and targeting SIRT3 may have revelatory implications in the treatment of cardiovascular diseases and the application of HiPSC-CMs to regenerative medicine.

更新日期：2022-12-31

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