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BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke.


ABSTRACT: 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. BNIP3, a pro-apoptotic BH3-only protein, has been implicated as a regulator of mitophagy. AIMS:Both in vivo and in vitro models of stroke, as well as BNIP3 wild-type and knock out mice were used in this study. RESULTS:We show that BNIP3 and its homologue BNIP3L (NIX) are highly expressed in a "delayed" manner and contribute to delayed neuronal loss following stroke. Deficiency in BNIP3 significantly decreases both neuronal mitophagy and apoptosis but increases nonselective autophagy following ischemic/hypoxic insults. The mitochondria-localized BNIP3 interacts with the autophagosome-localized LC3, suggesting that BNIP3, similar to NIX, functions as a LC3-binding receptor on mitochondria. Although NIX expression is upregulated when BNIP3 is silenced, up-regulation of NIX cannot functionally compensate for the loss of BNIP3 in activating excessive mitophagy. CONCLUSIONS:NIX primarily regulates basal level of mitophagy in physiological conditions, whereas BNIP3 exclusively activates excessive mitophagy leading to cell death.

SUBMITTER: Shi RY 

PROVIDER: S-EPMC6492992 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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