Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy

• Published in: Nature communications 2022-07, Vol.13 (1), p.3947-3947, Article 3947
• Main Authors: Wang, Xueqiang, Zhang, Xing, Cao, Ke, Zeng, Mengqi, Fu, Xuyang, Zheng, Adi, Zhang, Feng, Gao, Feng, Zou, Xuan, Li, Hao, Li, Min, Lv, Weiqiang, Xu, Jie, Long, Jiangang, Zang, Weijin, Chen, Jinghai, Ding, Jian, Liu, Jiankang, Feng, Zhihui
• Format: Article
• Language: English
• Subjects: 13/51; 13/89; 14/34; 14/63; 38/77; 38/91; 631/443/319; 64/60; 692/4019/592/75/230; 82/1; Assembly; Cardiac function; Cardiac muscle; Cardiomyopathy; Cardiovascular diseases; Congestive heart failure; Coronary artery disease; Dehydrogenase; Dehydrogenases; Dilated cardiomyopathy; Disruption; Dynamin; Fetuses; Fission; Heart diseases; Homeostasis; Humanities and Social Sciences; Life span; Metabolic rate; Mitochondria; multidisciplinary; Muscles; Myocardial infarction; Science; Science (multidisciplinary); Succinate dehydrogenase; Supplements; Therapeutic applications; Young adults
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31548-1

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.