Mitochondrial autophagy: Origins, significance, and role of BNIP3 and NIX

Abstract

Mitochondrial autophagy (mitophagy) is a core cellular activity. In this review, we consider mitophagy and related cellular processes and discuss their significance for human disease. Strong parallels exist between mitophagy and xenophagy employed in host defense. These mechanisms converge on receptors in the innate immune system in clinically relevant scenarios. Mitophagy is part of a cellular quality control mechanism, which is implicated in degenerative disease, especially neurodegenerative disease. Furthermore, mitophagy is an aspect of cellular remodeling, which is employed during development. BNIP3 and NIX are related multi-functional outer mitochondrial membrane proteins. BNIP3 regulates mitophagy during hypoxia, whereas NIX is required for mitophagy during development of the erythroid lineage. Recent advances in the field of BNIP3- and NIX-mediated mitophagy are discussed.

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

“…In cells treated with pathogen-associated molecular patterns (DAMPs) mitochondrial dysfunction has been observed, as well as the increase in ROS synthesis. These events activate mitochondrial permeability transition, which causes the leakage of mtDNA to the cytosol (Oka et al, 2012;Ney, 2015). Sun et al (2013) reported that mitochondrial DAMPs induce changes in endothelial permeability, suggesting that release of mitochondrial factors from dead or dying cells can be a critical factor in the early endothelial response to damage.…”

Regulation of mitophagy in ischemic brain injury

“…Both Bnip3 and Nix are primarily localized on the outer mitochondrial membrane, and share a similar mechanism to induce mitophagy (for reviews, see [80,81] ). The difference between the two proteins during the induction of mitophagy is of interest.…”

“…Bnip3 has been reported to participate in hypoxia-induced mitophagy in rat heart. Nix was fi rst found to be essential for the induction of mitophagy during the maturation of red blood cells [79] .Both Bnip3 and Nix are primarily localized on the outer mitochondrial membrane, and share a similar mechanism to induce mitophagy (for reviews, see [80,81] ). The difference between the two proteins during the induction of mitophagy is of interest.…”

Mitochondrial dynamics and quality control in Huntington's disease

“…Since mitophagy in yeast involves the interaction between cytosolic Atg11 and mitochondrial Atg32 (Kanki et al, 2015), and since the Htt C-terminal can interact with mammalian Atg32 homologues (BNIP3 and NIX), mammalian mitophagy is proposed to involve Htt-BNIP3/NIX interactions (Ochaba et al, 2014). Significantly, BNIP3 and NIX also interact with autophagosomal LC3, and while the BNIP3/NIX-associated mitophagy pathway has been primarily associated with reticulocyte maturation (Ney, 2015), recent evidence implicates this pathway in neuronal mitophagy (Shi et al, 2014). Thus, wild-type Htt may have a role in mitophagy that is disturbed by mHtt, nevertheless, whether and how N-terminal polyQ disturbs the interaction of the C-terminal with mitochondria remains undetermined.…”