Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.
Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.
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DOI：
10.1038/s41467-022-31548-1
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发表时间：
2022-07-08
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
琥珀酸脱氢酶被称为线粒体复合物II，已被证明是一种迷人的机制，吸引了人们对其参与人类疾病的新的和更大的兴趣。在此，我们发现琥珀酸脱氢酶组装因子4（SDHAF 4）在心肌中响应于病理应激和人类患者的患病心脏中下调。心脏损失的Sdl4抑制复合物II组装，并导致亚基降解和复合物II缺陷的胎鼠。这些缺陷在具有整体受损的代谢能力和动力蛋白相关蛋白1的活化的年轻人中加剧，动力蛋白相关蛋白1诱导过量的线粒体分裂和线粒体自噬，从而在动物中引起进行性扩张型心肌病和致死性心力衰竭。通过补充富马酸盐或抑制线粒体分裂来靶向线粒体可改善线粒体动力学，部分恢复心脏功能并延长突变小鼠的寿命。此外，发现富马酸盐的添加显著改善心肌梗死小鼠的心脏功能。这些研究结果揭示了复杂II组装在扩张型心肌病的发展中的重要作用，并为心脏病的治疗干预提供了额外的见解。功能性琥珀酸脱氢酶（SDH）复合物对线粒体内环境稳定至关重要。在这里，作者表明，心脏中SDH组装的破坏通过损害线粒体完整性和代谢引起扩张型心肌病，线粒体干预可能是改善疾病进展的有效方法。
Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases. Functional succinate dehydrogenase (SDH) complex is vital to mitochondrial homeostasis. Here the authors show that disruption of SDH assembly in the heart causes dilated cardiomyopathy via impairing the mitochondrial integrity and metabolism and that mitochondrial interventions can be an effective approach to ameliorate the disease progression.
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影响因子：
82.9
作者：
通讯作者：
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影响因子：
5.2
作者：
Levitas, Aviva;Muhammad, Emad;Parvari, Ruti
通讯作者：
Parvari, Ruti
DOI：
10.1002/ajmg.c.30289
发表时间：
2011-02-15
影响因子：
3.1
作者：
Erez, Ayelet;Nagamani, Sandesh C. Sreenath;Lee, Brendan
通讯作者：
Lee, Brendan
影响因子：
3.4
作者：
Aldera, Alessandro Pietro;Govender, Dhirendra
通讯作者：
Govender, Dhirendra
影响因子：
9.7
作者：
Daubert, Melissa A.;Yow, Eric;Sabbah, Hani N.
通讯作者：
Sabbah, Hani N.