Open AccessBNIP3 Interacting with LC3 Triggers Excessive Mitophagy in Delayed Neuronal Death in Stroke
Author(s) -
Shi RuoYang,
Zhu ShengHua,
Li Victor,
Gibson Spencer B.,
Xu XingShun,
Kong JiMing
Publication year - 2014
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12325
Subject(s) - mitophagy , autophagy , mitochondrion , microbiology and biotechnology , programmed cell death , apoptosis , biology , downregulation and upregulation , neuroscience , biochemistry , gene
Summary Introduction A basal level of mitophagy is essential in mitochondrial quality control in physiological conditions, while excessive mitophagy contributes to cell death in a number of diseases including ischemic stroke. Signals regulating this process remain unknown. BNIP 3, a pro‐apoptotic BH 3‐only protein, has been implicated as a regulator of mitophagy. Aims Both in vivo and in vitro models of stroke, as well as BNIP 3 wild‐type and knock out mice were used in this study. Results We show that BNIP 3 and its homologue BNIP 3L ( NIX ) are highly expressed in a “delayed” manner and contribute to delayed neuronal loss following stroke. Deficiency in BNIP 3 significantly decreases both neuronal mitophagy and apoptosis but increases nonselective autophagy following ischemic/hypoxic insults. The mitochondria‐localized BNIP 3 interacts with the autophagosome‐localized LC 3, suggesting that BNIP 3, similar to NIX , functions as a LC 3‐binding receptor on mitochondria. Although NIX expression is upregulated when BNIP 3 is silenced, up‐regulation of NIX cannot functionally compensate for the loss of BNIP 3 in activating excessive mitophagy. Conclusions NIX primarily regulates basal level of mitophagy in physiological conditions, whereas BNIP 3 exclusively activates excessive mitophagy leading to cell death.