A membrane arm of mitochondrial complex I sufficient to promote respirasome formation
Hezhi Fang,
Xianglai Ye,
Jie Xie,
Yuanyuan Li,
Haiyan Li,
Xinzhu Bao,
Yue Yang,
Zifan Lin,
Manli Jia,
Qing Han,
Jingjing Zhu,
Xueyun Li,
Qiongya Zhao,
Yanling Yang,
Jianxin Lyu
Affiliations
Hezhi Fang
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China; Corresponding author
Xianglai Ye
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Jie Xie
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Yuanyuan Li
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Haiyan Li
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Xinzhu Bao
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Yue Yang
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Zifan Lin
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Manli Jia
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Qing Han
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Jingjing Zhu
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Xueyun Li
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China
Qiongya Zhao
Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310000, China
Yanling Yang
Department of Pediatrics, Peking University First Hospital, Beijing 100000, China
Jianxin Lyu
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China; Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310000, China; Corresponding author
Summary: The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.
