Defective mitochondrial ISCs biogenesis switches on IRP1 to fine tune selective mitophagy
Hao Wu,
Huifang Wei,
Di Zhang,
Sheikh Arslan Sehgal,
Dejiu Zhang,
Xiaohui Wang,
Yan Qin,
Lei Liu,
Quan Chen
Affiliations
Hao Wu
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Corresponding author. Huazhong Agricultural University, China
Huifang Wei
China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450003, China; Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
Di Zhang
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100101, China
Sheikh Arslan Sehgal
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100101, China; COMSATS University, Islamabad, Sahiwal Campus, Pakistan
Dejiu Zhang
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Xiaohui Wang
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
Yan Qin
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Lei Liu
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Corresponding author. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, China
Quan Chen
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100101, China; Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China; Corresponding author. Nankai University, China
Both iron metabolism and mitophagy, a selective mitochondrial degradation process via autolysosomal pathway, are fundamental for the cellular well-being. Mitochondria are the major site for iron metabolism, especially the biogenesis of iron-sulfur clusters (ISCs) via the mitochondria-localized ISCs assembly machinery. Here we report that mitochondrial ISCs biogenesis is coupled with receptor-mediated mitophagy in mammalian cells. Perturbation of mitochondrial ISCs biogenesis, either by depleting iron with the iron chelator or by knocking down the core components of the mitochondrial ISCs assembly machinery, triggers FUNDC1-dependent mitophagy. IRP1, one of the cellular iron sensors to maintain iron homeostasis, is crucial for iron stresses induced mitophagy. Knockdown of IRP1 disturbed iron stresses induced mitophagy. Furthermore, IRP1 could bind to a newly characterized IRE in the 5’ untranslated region of the Bcl-xL mRNA and suppress its translation. Bcl-xL is an intrinsic inhibitory protein of the mitochondrial phosphatase PGAM5, which catalyzes the dephosphorylation of FUNDC1 for mitophagy activation. Alterations of the IRP1/Bcl-xL axis navigate iron stresses induced mitophagy. We conclude that ISCs serve as physiological signals for mitophagy activation, thus coupling mitophagy with iron metabolism.
