Embryonic retinal development
03 May 2017
Mitophagy regulates cell differentiation by reprogramming metabolism

A recent study published in EMBO J. by the group of Dr. Patricia Boya from CIB shows that mitophagy (a type of selective autophagy by which mitochondria are specifically degraded and recycled) is capable of altering the metabolic profile of the cells displacing it towards glycolysis regulating processes of cellular differentiation, and constitutes a new mechanism of metabolic reprogramming.
The metabolic processes by which the cells get their energy are of several types. In general, cells use glycolysis coupled to oxidative phosphorylation, the latter process that occurs in mitochondria. Certain cell types do not use mitochondria and derive all their energy through glycolysis, from glucose conversion to lactate. For example, cancer cells use the fast rate of glycolysis for energy production to sustain high rate of cell division. However, differentiated cells (specialized for a given function) are more specialized and use oxidative phosphorylation.
Another paradigm of metabolic reprogramming is when macrophages become proinflammatory (M1), which also use the energy of glycolysis to develop a fast immune response. In this work, carried out with international collaboration, mitophagy inhibition reverses this proinflammatory phenotype of M1 macrophages. In addition, the differentiation of retinal ganglion cells is reduced after mitophagy inhibition due to reduced glycolysis. Moreover, the article also shows that during retinal development physiological hypoxia is the cause of mitophagy and glycolytic shift that supports neuronal differentiation.
This metabolic control by autophagy and mitophagy could be of importance to potentiate the generation of ganglion cells from stem cells with a possible application in the treatment of diseases like the glaucoma, that is characterized by the loss of ganglion cells and their axons. In fact, one of the first symptoms of some mitochondrial diseases is the loss of vision associated with alterations in ganglion cells, and it is known that these cells are very dependent of proper mitochondrial function.
On the other hand, "the molecular mechanisms of death of retinal ganglion cells, which degenerate in glaucoma, are not yet known but a way to promote the mitochondrial quality of the same modulating mitophagy, could be used to find new therapies for this disease," states Patricia Boya, author of this study. This would not be the only pathology in which this mechanism may be important. Also diabetes, and other metabolic or nervous system diseases could benefit from the modulation of the activity of macrophages and other cell types through autophagy.

This work has been carried out with the international collaboration of researchers from the Albert Einstein College of Medicine (New York), the National Center for Oncological Research (Madrid), the Foundation for Health Research of the Principality of Asturias (Oviedo), Metabolomics and Molecular Cell Biology Platforms (Villejuif) and the Center de Recherche des Cordeliers.

Reference: 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. The EMBO Journal (2017). DOI 10.15252/embj.201695916


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Article commentary in Autophagy Journal: BNIP3L/NIX-dependent mitophagy regulates cell differentiation via metabolic reprogramming. Lorena Esteban-Martínez, Patricia Boya.