BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains

Wu, Xiaoli1; Zheng, Yanrong1; Liu, Mengru1; Li, Yue1; Ma, Shijia1; Tang, Weidong1; Yan, Wenping2; Cao, Ming1; Zheng, Wanqing1; Jiang, Lei1; Wu, Jiaying2; Han, Feng3; Qin, Zhenghong4,5; Fang, Liang6,7; Hu, Weiwei1; Chen, Zhong1; Zhang, Xiangnan1

2020-08-13

10.1080/15548627.2020.1802089

Autophagy   影响因子和分区

1554-8627

1554-8635

Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished inbnip3l(-/-)mice. Taken together, the present study linked BNIP3L degradation by proteasomes with mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation.

BNIP3L NIX carfilzomib cerebral ischemia mitophagy ubiquitin-proteasome pathway

SCI

英语

其他

National Natural Science Foundation of China[81822044][81773703][81872844] ; Fundamental Research Funds for the Central Universities[2019XZZX004-17]

Cell Biology

Cell Biology

WOS:000558501800001

TAYLOR & FRANCIS INC

Web of Science

1.Zhejiang Univ, Minist Hlth China, Key Lab Med Neurobiol, Inst Pharmacol & Toxicol,Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
2.Zhejiang Univ, Affiliated Hosp 1, Coll Med, Hangzhou, Peoples R China
3.Nanjing Med Univ, Sch Pharm, Key Lab Cardiovasc & Cerebrovasc Med, Nanjing, Peoples R China
4.Soochow Univ, Dept Pharmacol, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Sch Pharmaceut Sci, Suzhou, Peoples R China
5.Soochow Univ, Lab Aging & Nervous Dis, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Sch Pharmaceut Sci, Suzhou, Peoples R China
6.Southern Univ Sci & Technol, Acad Adv Interdisciplinary Studies, Shenzhen, Peoples R China
7.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China

Wu, Xiaoli,Zheng, Yanrong,Liu, Mengru,et al. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains[J]. Autophagy,2020.

Wu, Xiaoli.,Zheng, Yanrong.,Liu, Mengru.,Li, Yue.,Ma, Shijia.,...&Zhang, Xiangnan.(2020).BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains.Autophagy.

Wu, Xiaoli,et al."BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains".Autophagy (2020).