Abstract
In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays 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 bioenergetic functions 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 mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergetic demand of the tumor. In this review, after a brief introduction of the main mitophagy regulators 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 mitophagy in the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses.
Highlights
Mitochondria are double-membrane organelles deputed at cell energy supply; defects in mitochondrial functions affect cell homeostasis, bioenergetics and redox control and are decisive for cell death
The role of FIS1 in mitochondrial fission is controversial, since it was initially described an outer mitochondrial membrane (OMM)-anchored receptor assisting the mitochondrial localization of dynamin-related protein 1 (DRP1) [25] but recent data showed that FIS1 can induce mitochondrial fragmentation by inhibiting the GTP-ase activity of the fusion machinery (MFN1, MFN2 and Opa1) [26]
Among various selective degradation pathways operating in mammalian cells, mitophagy is emerging as a crucial determinant of cancer cell plasticity and interface with the tumor microenvironment (TME)
Summary
Mitochondria are double-membrane organelles deputed at cell energy supply; defects in mitochondrial functions affect cell homeostasis, bioenergetics and redox control and are decisive for cell death. A tight control of the mitochondrial network homeostasis is essential for cancer cells. Several highly interrelated mechanisms, including mitochondrial dynamics (fusion and fission) as well as macroautophagy (mitophagy), operate in mammalian cells as key mitochondrial quality control processes, and their implication in tumor development and progression has recently been elucidated. The selective removal of mitochondria through the process of mitophagy has been recently implicated in reshaping the metabolic landscape within cancer cells and the interaction between cancer cells and other key components of the tumor microenvironment (TME), to foster the adaptive and survival ability of cancer cells. Considering the tight relationship between mitochondrial homeostasis and susceptibility to cell death, mitochondria quality control and mitophagy in primis are critical in anti-cancer therapeutic response as well as cancer-related off target effects. After a brief introduction of the main mitophagy pathways, we discuss the interplay of mitophagy with the key pathways involved in tumorigenesis, its coordination of the TME and its implication in the success (or not) of current anti-cancer therapies
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