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Programmed mitophagy is essential for the glycolytic switch during cell differentiation
Author(s) -
EstebanMartínez Lorena,
SierraFilardi Elena,
McGreal Rebecca S,
SalazarRoa María,
Mariño Guillermo,
Seco Esther,
Durand Sylvère,
Enot David,
Graña Osvaldo,
Malumbres Marcos,
Cvekl Ales,
Cuervo Ana María,
Kroemer Guido,
Boya Patricia
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695916
Subject(s) - biology , mitophagy , cellular differentiation , microbiology and biotechnology , glycolysis , genetics , autophagy , metabolism , biochemistry , apoptosis , gene
Retinal ganglion cells ( RGC s) 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 BCL 2/adenovirus E1B 19‐ kD a‐interacting protein 3‐like ( BNIP 3L, 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.