Mitophagy in tumorigenesis and metastasis

• Published in: Cellular and molecular life sciences : CMLS Vol. 78; no. 8; pp. 3817 - 3851
• Main Authors: Poole, Logan P., Macleod, Kay F.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2021; Springer Nature B.V
• Subjects: Animals; Atrophy; autophagosomes; Biochemistry; Biomedical and Life Sciences; Biomedicine; BNIP3 protein; Cachexia; Cancer; carcinogenesis; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cardiolipin; cardiolipins; Cell Biology; Cell cycle; Cell migration; cell movement; Cell survival; Ceramide; ceramides; Deprivation; Extracellular matrix; family; GABARAP protein; Humans; Hypoxia; Life Sciences; Lipids; Metastases; Metastasis; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Damage Control; Mitochondrial DNA; Mitochondrial Dynamics; mitochondrial proteins; Mitophagy; Modulators; Neoplasm Metastasis - pathology; Neoplasms - metabolism; Neoplasms - pathology; Parkin protein; Phagosomes; Prohibitin; PTEN-induced putative kinase; Review; Signal transduction; Signaling; Sirtuins; Sphingosine 1-phosphate; Stresses; therapeutics; Tumorigenesis; Ubiquitination; Sirtuins; Mitohormesis; BNIP3/BNIP3L; LC3/GABARAP; PARP; Cachexia; Metastasis; Mitophagy; Metabolism; Autophagy; Fission; DRP1; Electron transport chain; NAD; Mitochondria; PINK1/Parkin; BCL2-L-13; FUNDC1; UPR; ROS; AMPK; Respiration; FoxOs; ATF4; UPRmt
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-021-03774-1

Cells use mitophagy to remove dysfunctional or excess mitochondria, frequently in response to imposed stresses, such as hypoxia and nutrient deprivation. Mitochondrial cargo receptors (MCR) induced by these stresses target mitochondria to autophagosomes through interaction with members of the LC3/GABARAP family. There are a growing number of these MCRs, including BNIP3, BNIP3L, FUNDC1, Bcl2-L-13, FKBP8, Prohibitin-2, and others, in addition to mitochondrial protein targets of PINK1/Parkin phospho-ubiquitination. There is also an emerging link between mitochondrial lipid signaling and mitophagy where ceramide, sphingosine-1-phosphate, and cardiolipin have all been shown to promote mitophagy. Here, we review the upstream signaling mechanisms that regulate mitophagy, including components of the mitochondrial fission machinery, AMPK, ATF4, FoxOs, Sirtuins, and mtDNA release, and address the significance of these pathways for stress responses in tumorigenesis and metastasis. In particular, we focus on how mitophagy modulators intersect with cell cycle control and survival pathways in cancer, including following ECM detachment and during cell migration and metastasis. Finally, we interrogate how mitophagy affects tissue atrophy during cancer cachexia and therapy responses in the clinic.