Reference

DOI 10.15252/embj.201695916 | The EMBO Journal (2017) e201695916 embomay2017

Authors

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 y Patricia Boya.

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.

Description

La degradación de mitocondrias por autofagia o mitofagia, es esencial para producir una reprogramación metabólica hacia glicolisis que es necesaria para la diferenciación de las células ganglionares de la retina. Este proceso de mitofagia programada está regulado por NIX, un receptor de mitofagia cuya expresión incrementa por la hipoxia del tejido en desarrollo.

 

 

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REFERENCIA DEL GRUPO INVESTIGADOR

El laboratorio de Patricia Boya en el CIB-CSIC estudia por qué la autofagia es esencial para la correcta función de nuestras células y tejidos. Su trabajo se centra en entender las relaciones entre la autofagia y los procesos básicos como la proliferación, la diferenciación y la muerte celular y cómo alteraciones en autofagia pueden subyacer tras ciertas patologías como el cáncer y las enfermedades neurodegenerativas.

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