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

Xueqiang Wang, Xing Zhang, Ke Cao, Mengqi Zeng, Xuyang Fu, Adi Zheng, Feng Zhang, Feng Gao, Xuan Zou, Hao Li, Min Li, Weiqiang Lv, Jie Xu, Jiangang Long, Weijin Zang, Jinghai Chen, Feng Gao, Jian Ding (), Jiankang Liu () and Zhihui Feng ()
Additional contact information
Xueqiang Wang: University of Health and Rehabilitation Sciences
Xing Zhang: Fourth Military Medical University
Ke Cao: Xi’an Jiaotong University
Mengqi Zeng: Xi’an Jiaotong University
Xuyang Fu: Zhejiang University School of Medicine
Adi Zheng: Xi’an Jiaotong University
Feng Zhang: Zhejiang University School of Medicine
Feng Gao: Zhejiang University School of Medicine
Xuan Zou: The Second Affiliated Hospital of Xi’an Jiaotong University
Hao Li: Xi’an Jiaotong University
Min Li: Fourth Military Medical University
Weiqiang Lv: Xi’an Jiaotong University
Jie Xu: Xi’an Jiaotong University
Jiangang Long: Xi’an Jiaotong University
Weijin Zang: Xi’an Jiaotong University Health Science Center
Jinghai Chen: Zhejiang University School of Medicine
Feng Gao: Fourth Military Medical University
Jian Ding: Xi’an Jiaotong University
Jiankang Liu: University of Health and Rehabilitation Sciences
Zhihui Feng: University of Health and Rehabilitation Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31548-1

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