Mitophagy and cancer

Abstract

Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

Impaired mitophagy activates mtROS/HIF-1α interplay and increases cancer aggressiveness in gastric cancer cells under hypoxia

“…In addition to the core factors in the autophagy, previous studies have revealed that specific regulators such as BNIP3, NIX, Parkin, Pink1 and FUNDC1 are required for promoting mitophagy (31,(34)(35)(36). Recently, emerging evidence has revealed that deregulation in key regulators of mitophagy is found in several cancers and suggested a possible implication in tumorigenesis (34). For instance, Parkin located at human chromosome 6q25-q26 is frequently deleted in bladder, lung, breast and ovarian cancers.…”

“…Mitochondrial autophagy, designated as mitophagy, is a selective form of autophagy in which mitochondria are degraded in autolysosomes (31,32). Mitophagy represents a critical adaptive mechanism to maintain oxygen homeostasis and to eliminate old and/or damaged mitochondrion in response to certain stresses including hypoxia (33,34). In addition to the core factors in the autophagy, previous studies have revealed that specific regulators such as BNIP3, NIX, Parkin, Pink1 and FUNDC1 are required for promoting mitophagy (31,(34)(35)(36).…”

“…Mitophagy represents a critical adaptive mechanism to maintain oxygen homeostasis and to eliminate old and/or damaged mitochondrion in response to certain stresses including hypoxia (33,34). In addition to the core factors in the autophagy, previous studies have revealed that specific regulators such as BNIP3, NIX, Parkin, Pink1 and FUNDC1 are required for promoting mitophagy (31,(34)(35)(36). Recently, emerging evidence has revealed that deregulation in key regulators of mitophagy is found in several cancers and suggested a possible implication in tumorigenesis (34).…”

BRCA2 functions: from DNA repair to replication fork stabilization

“…Although BRCA2 functions have so far taken place in the nucleus, a recent study raises the intriguing possibility that BRCA2, along with BRCA1 and multiple proteins of the FA pathway (FANCA, FANCF, FANCL, FANCD2), facilitates mitophagy, a cytoplasmic process that targets damaged mitochondria to selective autophagy (Sumpter et al 2016). Mitophagy is critical to maintain low level of mitochondrial reactive oxygen species (mtROS), and recent evidence suggests that the accumulation of mtROS impacts transformation and tumors progression (Chourasia et al 2015). Therefore, understanding BRCA2 functions in the cytoplasm may shed new light on its role as a tumor suppressor.…”

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

“…An alternative mechanism ( Figure 2B), most well studied during hypoxia-induced mitophagy involves two molecular regulators, BNIP3 and NIX (Zhang and Ney, 2009), which are targets of the hypoxia inducible factors (HIFS) (Guo et al, 2001) as well as other transcription factors including NFkB and P53 (Fei et al, 2004;Feng et al, 2011;Shaw et al, 2008) Inhibition or disruption of BNIP3/NIX function can lead to non-apoptotic cell death suggesting their roles in quality control are critical (Chourasia et al, 2015).…”