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Highlights d Cardiomyocytes release subcellular particles called exophers d Cardiac exophers transport defective mitochondria for elimination d cMacs capture and eliminate exophers though Mertk

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

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.

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Macroautophagy/autophagy is the process by which cellular components are degraded and recycled within the lysosome. These components include mitochondria, the selective degradation of which is known as mitophagy. Mitochondria are dynamic organelles that constantly adapt their morphology, function, and number to accommodate the metabolic needs of the cell. Extensive metabolic reconfiguration occurs during cell differentiation, when mitochondrial activity increases in most cell types. However, our data demonstrate that during physiologic retinal ganglion cell (RGC) development, mitophagy-dependent metabolic reprogramming toward glycolysis regulates numbers of RGCs, which are the first neurons to differentiate in the retina and whose axons form the optic nerve. We show that during retinal development tissue hypoxia triggers HIF1A/HIF-1 stabilization, resulting in increased expression of the mitophagy receptor BNIP3L/NIX. BNIP3L-dependent mitophagy results in a metabolic shift toward glycolysis essential for RGC neurogenesis. Moreover, we demonstrate that BNIP3L-dependent mitophagy also regulates the polarization of proinflammatory/M1 macrophages, which undergo glycolysis-dependent differentiation during the inflammatory response. Our results uncover a new link between hypoxia, mitophagy, and metabolic reprogramming in the differentiation of several cell types in vivo. These findings may have important implications for neurodegenerative, metabolic and other diseases in which mitochondrial dysfunction and metabolic alterations play a prominent role.