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.

Keywords: autophagy; metabolic reprogramming; mitophagy; retina; retinal ganglion cells.

Figure 1.

Mitophagy-dependent metabolic reprogramming during cell differentiation. Retinal neuroblasts and undifferentiated macrophages contain an increased number of mitochondria and display an oxidative phosphorylation metabolic profile, which enables the production of high levels of ATP via glucose oxidation. High levels of respiration in the developing retina and in inflamed tissue lead to decreased oxygen availability, triggering a hypoxia response coordinated by the transcription factor HIF1A. One target of HIF1A is the mitophagy receptor BNIP3L/NIX, which mediates the formation of phagophores and mitochondria engulfment within autophagosomes for subsequent degradation in the lysosome. This reduction in mitochondrial number triggers a metabolic switch whereby glucose is metabolized to lactate, which is required for RGC neurogenesis and M1 macrophage polarization.