Programmed mitophagy is essential for the glycolytic switch during cell differentiation

Lorena Esteban-Martínez, 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

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64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1688-1706
Number of pages19
JournalEMBO Journal
Volume36
Issue number12
DOIs
StatePublished - Jun 14 2017

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Keywords

  • BNIP3L/NIX
  • hypoxia
  • macrophages
  • metabolic reprogramming
  • retinal ganglion cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Esteban-Martínez, L., Sierra-Filardi, E., McGreal, R. S., Salazar-Roa, M., Mariño, G., Seco, E., Durand, S., Enot, D., Graña, O., Malumbres, M., Cvekl, A., Cuervo, A. M., Kroemer, G., & Boya, P. (2017). Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO Journal, 36(12), 1688-1706. https://doi.org/10.15252/embj.201695916