Mitophagy in Cancer: A Tale of Adaptation

In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cellsplays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial functions have been shown to be crucial for both cancer and stromal cells. This is perhaps not surprising, considering that mitochondria in both cancerous and non-cancerous cells are decisive for vital metabolic and bioenergeticfunctions and to elicit cell death. The central part played by mitochondria also implies the existence of stringent mitochondrial quality control mechanisms, where a specialized autophagy pathway ( mitophagy) ensures the selective removal of damaged or dysfunctional mitochondria. Although the molecular underpinnings of mitophagyregulation in mammalian cells remain incomplete, it is becoming clear that mitophagypathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergeticdemand of the tumor. In this review, after a brief introduction of the main mitophagyregulators operating in mammalian cells, we discuss emerging cell autonomous roles of mitochondria quality control in cancer onset and progression. We also discuss the relevance of mitophagyin the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses.