Programmed mitophagy is essential for the glycolytic switch during cell differentiation

• DOI: 10.15252/embj.201695916
• Publication Date: 2017-05-03T00:10:32Z
• Authors: Lorena Esteban‐Ma...; Elena Sierra‐Filardi; Rebecca S McGreal; María Salazar‐Roa; Guillermo Mariño; Esther Seco; Sylvère Durand; David Enot; Osvaldo Graña; Marcos Malumbres; Ales Cvekl; Ana María Cuervo; Guido Kroemer; Patricia Boya
• Keywords: Mice, Knockout; Retinal Ganglion Cells; Macrophages; Metabolic reprogramming; Mitophagy; Membrane Proteins; Cell Differentiation; Retinal ganglion cells; Retina; 3. Good health; Mitochondrial Proteins; Mice; Animals; BNIP3L/NIX; Hypoxia; Glycolysis

Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L, best known as NIX) at peak RGC differentiation. Retinas from NIX-deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. Similarly, we provide evidence that NIX-dependent mitophagy contributes to mitochondrial elimination during macrophage polarization towards the proinflammatory and more glycolytic M1 phenotype, but not to M2 macrophage differentiation, which primarily relies on oxidative phosphorylation. In summary, developmentally controlled mitophagy promotes a metabolic switch towards glycolysis, which in turn contributes to cellular differentiation in several distinct developmental contexts.