TitleProgrammed mitophagy is essential for the glycolytic switch during cell differentiation.
Publication TypeJournal Article
Year of Publication2017
AuthorsEsteban-Martínez L, Sierra-Filardi E, McGreal RS, Salazar-Roa M, Mariño G, Seco E, Durand S, Enot D, Graña O, Malumbres M, Cvekl A, Cuervo AMaria, Kroemer G, Boya P
JournalEMBO J
Volume36
Issue12
Pagination1688-1706
Date Published2017 06 14
ISSN1460-2075
KeywordsAnimals, Cell Differentiation, Glycolysis, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Degradation, Mitochondrial Proteins, Retina, Retinal Ganglion Cells
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.

DOI10.15252/embj.201695916
Alternate JournalEMBO J.
PubMed ID28465321
PubMed Central IDPMC5470043
Grant ListR01 EY012200 / EY / NEI NIH HHS / United States
P30 DK041296 / DK / NIDDK NIH HHS / United States
R37 AG021904 / AG / NIA NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
R01 EY014237 / EY / NEI NIH HHS / United States
P30 CA013330 / CA / NCI NIH HHS / United States
P01 AG031782 / AG / NIA NIH HHS / United States