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Review
, 16 (7), 939-46

Role of BNIP3 and NIX in Cell Death, Autophagy, and Mitophagy

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Review

Role of BNIP3 and NIX in Cell Death, Autophagy, and Mitophagy

J Zhang et al. Cell Death Differ.

Abstract

BNIP3 and NIX are proteins related to the BH3-only family, which induce both cell death and autophagy. Consistent with their ability to induce cell death, BNIP3 and NIX are implicated in the pathogenesis of cancer and heart disease. In tumor cells, BNIP3 and NIX are regulated by hypoxia, and the deregulation of BNIP3 or NIX expression is associated with tumor growth. In heart muscle, BNIP3 and NIX are regulated by hypoxia and Galphaq-dependent signaling, respectively, and their expression is associated with decreased myocardial function. Apart from their role in cell death, BNIP3 and NIX are also implicated in the induction of autophagy. In erythroid cells, NIX is required for a specialized type of autophagy that targets mitochondria for elimination (mitophagy). Similarly, BNIP3 regulates mitophagy in response to hypoxia. In this review, we will discuss possible mechanisms by which BNIP3 and NIX induce cell death and mitophagy. We will also consider the potential relationship between cell death pathways and autophagy in development and homeostasis.

Figures

Figure 1
Figure 1
BH3 domain alignment. An alignment of the BH3 domains of human BNIP3, NIX, other BH3-only proteins, and Beclin-1 is shown. Hydrophobic nonpolar residues are highlighted in olive, hydrophobic polar residues in gray, negatively charged residues in red, and positively charged residues in teal. Conserved tryptophan residues in BNIP3 and NIX are shown in bold. BH3 residues that are partially or fully buried when bound to BCL-XL are indicated by an “X” at the top. Critical helical contact residues in Beclin-1 that disrupt the interaction with BCL-XL (L, G), or BCL2 (F), when mutated are shown in bold. The first leucine residue in each row corresponds to position 1 in ref. .
Figure 2
Figure 2
Potential mechanisms of BNIP3 and NIX-induced cell death. (Left panel) BNIP3 (blue box) or NIX (teal box), in concert with BAX or BAK (plum box), cause opening of the MPTP (lime oval), mitochondrial depolarization (represented as gray color), increased generation of reactive oxygen species, and cell death. (Center panel) BNIP3 or NIX bind BCL2 or BCL-XL (black box), releasing BH3-only protein (orange box) to interact with BAX or BAK, causing cytochrome c release, caspase activation, and cell death. (Right panel) NIX binds to endoplasmic reticulum/sarcoplasmic reticulum (ER/SR), increasing ER/SR calcium (Ca++) stores, causing mitochondrial calcium uptake, opening of the MPTP, and cell death.
Figure 3
Figure 3
NIX is required for mitophagy in reticulocytes. (Top panel set) Mitochondria in wild type reticulocytes undergoing exocytosis. Mitochondria in mature autophagic vacuoles (left two panels). Elimination of individual mitochondria (right three panels). (Bottom panel set) Mitochondria in Nix−/− reticulocytes accumulate on the cytoplasmic face of autophagosomes, but are not eliminated. A 0.5 µm bar is shown for scale in all panels. Magnification is 25,000× in all panels, except in the upper panel set the left two panels are 75,000×, and the upper right panel is 50,000×.
Figure 4
Figure 4
Potential mechanisms of NIX-dependent mitophagy in reticulocytes. (Top row, left panel) NIX (teal box) opens non-MPTP pore (lavender oval), causing mitochondrial depolarization (represented as gray color), and inducing mitophagy. (Top row, center panel) NIX recruits autophagy protein (orange oval), which supports formation of phagophore. (Top row, right panel) NIX binds BCL-XL (black box), BCL-XL releases Beclin-1 (red box), which activates autophagy, and supports formation of phagophore. (Middle row) Completed autophagosome matures into autophagic vacuole (AV), and mitochondria is degraded. Depending on the mechanism, mitochondrial depolarization either occurs prior to this step or at this step. (Bottom row) A degraded mitochondria is eliminated by exocytosis. A legend is shown at the bottom.

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