RT Journal Article
T1 Programmed mitophagy is essential for the glycolytic switch during cell differentiation
A1 Esteban-Martínez, Lorena
A1 Sierra-Filardi, Elena
A1 McGreal, Rebecca
A1 Salazar Roa, María
A1 Mariño, Guillermo
A1 Seco, Esther
A1 Durand, Sylvère
A1 Enot, David
A1 Graña, Osvaldo
A1 Malumbres, Marcos
A1 Cvekl, Ales
A1 Cuervo, Ana María
A1 Kroemer, Guido
A1 Boya, Patricia
AB 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.
PB EMBO Press
SN 0261-4189
YR 2017
FD 2017
LK https://hdl.handle.net/20.500.14352/97879
UL https://hdl.handle.net/20.500.14352/97879
LA eng
NO Esteban‐Martínez, Lorena, et al. «Programmed Mitophagy Is Essential for the Glycolytic Switch during Cell Differentiation». The EMBO Journal, vol. 36, n.o 12, junio de 2017, pp. 1688-706. https://doi.org/10.15252/embj.201695916.
NO AcknowledgementsResearch in P.B. laboratory is supported by grants BFU2015‐65623, BFU2015‐71869‐REDT from Spain's Ministerio de Economía y Competitividad and I‐link 0701 (to P.B. and A.M.C.) from CSIC. L.E.M. was recipient of a JAE‐Pre grant from CSIC. G.M. is funded by the Ramón y Cajal Program (RYC‐2013‐12751), supported by Spain's Ministerio de Economía y Competitividad (BFU2015‐68539) and the BBVA Foundation (BBM_BIO_3105). GK is supported by the Ligue Contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR)—Projets blancs; ANR under the framework of E‐Rare‐2, the ERA‐Net for Research on Rare Diseases; Association Pour la Recherche sur le Cancer (ARC); Cancéropôle Ile‐de‐France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno‐Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). A.C. research is supported by NIH grants EY012200 and EY014237. M.S.R. was supported by the Asociación Española contra el Cáncer (AECC, AIOA120833SALA). Work in the M.M. laboratory was supported by grants from the MINECO: (SAF2015‐69920‐R), Consolider‐Ingenio 2010 Programme (SAF2014‐57791‐REDC), Excellence Network CellSYS (BFU2014‐52125‐REDT) and the OncoCycle Programme (S2010/BMD‐2470) from the Comunidad de Madrid. We thank N. Marsh‐Armstrong and S. Martin‐Puig for reagents; O. Howard for English‐language editing; M. Casas for graphical abstract artwork; E. Rial for reagents and Seahorse analysis; and A. Corbi, T. Suárez, H.L. Vieira, A. Zorzano, J.M. Sanchez‐Puelles, M. Morán, I. Lopez‐Sanchez and I. Trounce for discussion.
NO Ministerio de Economía y Competitividad (España)
NO Ministerio de Ciencia e Innovación  (España)
NO Consejo Superior de Investigaciones Científicas
NO LeDucq Foundation
NO Paris Alliance of Cancer Research Institutes
NO National Institutes of Health
NO Asociación Española contra el Cáncer
NO Comunidad de Madrid
NO National Institute Against Cancer (France)
NO National Resarch Agency (France)
NO Foundation for Medical Research (France)
NO European Research Council
DS Docta Complutense
RD 18 dic 2025