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EMBO J. 2017 Jun 14;36(12):1688-1706. doi: 10.15252/embj.201695916. Epub 2017 May 2.

Programmed mitophagy is essential for the glycolytic switch during cell differentiation.

Author information

1
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
2
Departments of Genetics, Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
4
Departamento de Biología Fundamental, Universidad de Oviedo Fundación para la Investigación Sanitaria del Principado de Asturias (FINBA), Oviedo, Spain.
5
Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif, France.
6
Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
7
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA.
8
Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers, Paris, France.
9
INSERM, U1138, Paris, France.
10
Université Paris Descartes Sorbonne Paris Cité, Paris, France.
11
Université Pierre et Marie Curie, Paris, France.
12
Pôle de Biologie, Hôpital Européen Georges Pompidou AP-HP, Paris, France.
13
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
14
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain patricia.boya@csic.es.

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.

KEYWORDS:

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

PMID:
28465321
PMCID:
PMC5470043
DOI:
10.15252/embj.201695916
[Indexed for MEDLINE]
Free PMC Article

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