BNIP3L/NIX-dependent mitophagy regulates cell differentiation via metabolic reprogramming

Abstract

Macroautophagy/autophagy is the process by which cellular components are degraded and recycled within the lysosome. These components include mitochondria, the selective degradation of which is known as mitophagy. Mitochondria are dynamic organelles that constantly adapt their morphology, function, and number to accommodate the metabolic needs of the cell. Extensive metabolic reconfiguration occurs during cell differentiation, when mitochondrial activity increases in most cell types. However, our data demonstrate that during physiologic retinal ganglion cell (RGC) development, mitophagy-dependent metabolic reprogramming toward glycolysis regulates numbers of RGCs, which are the first neurons to differentiate in the retina and whose axons form the optic nerve. We show that during retinal development tissue hypoxia triggers HIF1A/HIF-1 stabilization, resulting in increased expression of the mitophagy receptor BNIP3L/NIX. BNIP3L-dependent mitophagy results in a metabolic shift toward glycolysis essential for RGC neurogenesis. Moreover, we demonstrate that BNIP3L-dependent mitophagy also regulates the polarization of proinflammatory/M1 macrophages, which undergo glycolysis-dependent differentiation during the inflammatory response. Our results uncover a new link between hypoxia, mitophagy, and metabolic reprogramming in the differentiation of several cell types in vivo. These findings may have important implications for neurodegenerative, metabolic and other diseases in which mitochondrial dysfunction and metabolic alterations play a prominent role.

Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3‐induced mitophagy

“…Another study demonstrated that in the first neurons to differentiate in the retina, the mitophagy receptor BNIP3L/NIX increased. These results indicate that mitochondrial dysfunction may play a prominent role …”

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…Moreover, nonautophagic mechanisms may also promote mitochondrial removal during reticulocyte maturation . NIX/BNIP3L and BNIP3, which are regulated by hypoxia‐inducible factor (HIF) or forkhead homeobox type O (FOXO), also participate in the hypoxia‐induced mitophagy …”

“…40 NIX/ BNIP3L and BNIP3, which are regulated by hypoxia-inducible factor (HIF) or forkhead homeobox type O (FOXO), also participate in the hypoxia-induced mitophagy. 41 While the upregulation of NIX or BNIP3 can enhance their activities in mitophagy, the interplay between BNIP3 and LC3 may also act at the level of phosphorylation of BNIP3. When Ser17 and Ser24 adjacent to the LIRs of BNIP3 are phosphorylated, the interplay between BNIP3 and LC3 is enhanced, suggesting a possible role of kinases or phosphatases in regulating mitophagy.…”

Programmed Switch in The Mitochondrial Degradation Pathways During Human Retinal Ganglion Cell Differentiation from Stem Cells is Critical for RGC Survival

“…Several studies in mice have shown programmed mitophagy is required for RGC differentiation [28,29], and an E50K mutation in the autophagy adaptor protein optineurin (OPTN) has been shown to cause mitochondrial accumulation and RGC death [30]. Additionally, OPTN E50K mutation was also found in the severe form of normal-tension glaucoma (NTG) patients [31].…”