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.

Keywords: Autophagosomes; BNIP3; Mitochondrial dysfunction; Mitophagy; NIX; Parkin.

Figure 1

Parkin recruitment to depolarized mitochondria promotes their degradation by mitophagy. In polarized mitochondria, PINK1 is degraded in the mitochondrial matrix (left), but upon membrane depolarization, PINK1 is stabilized and accumulates at the OMM, where it phosphorylates Mfn-2 and other substrates, including ubiquitin, that act as receptors for Parkin. Once Parkin is recruited to the OMM, it ubiquitinates key protein substrates including VDAC1 and Mfn-2, and other possibly unknown targets (substrate X). Parkin-dependent ubiquitination of VDAC1 and other mitochondrial proteins promotes interaction with p62/Sqstm1 that in turn facilitates interaction with LC3 at nascent phagophores thereby targeting depolarized mitochondria for degradation by autophagy.

Figure 2

BNIP/NIX promotes mitophagy through direct interaction with LC3 at the phagophore. BNIP3 and NIX are both hypoxia-inducible genes that encode molecular adaptors that promote mitophagy through interaction with processed LC3-related molecules at nascent phagophores (A). Both BNIP3 and NIX interact with Bcl-2 and Bcl-XL through their amino terminal ends, and Bcl-2/Bcl-XL has been postulated to play both positive and negative regulatory effects on BNIP3 function (A). BNip3 has also been shown to interact with regulators of mitochondrial fission (Drp-1) and mitochondrial fusion (Opa-1). These interactions are positive and negative, respectively, resulting in a role for BNIP3 in promoting fission while inhibiting fusion (B). BNIP3 has also been shown to interact with the small GTPase, Rheb, resulting in reduced Rheb activity, reduced mTOR activity, and reduced cell growth (C). This function for BNIP3 in modulating Rheb (C) contrasts with the proposed functional interaction of NIX with Rheb (D) that elicits a mTOR-independent effect on mitophagy by promoting LC3 processing and increased mitochondrial turnover in cells grown on oxidative substrates (D). NIX is required for recruitment of Rheb to mitochondria and its activating effect on mitophagy.

Figure 3

Strategies to target mitophagy for cancer therapy. Tumor cells are likely to be more dependent on functional mitophagy than normal cells due the increased requirement to manage ROS levels, due to dependence on key aspects of mitochondrial metabolism, such as glutaminolysis, particularly given the ischemic nature of advanced macroscopic tumors. Such a dependence on mitophagy could be exploited therapeutically by the development of specific small molecule inhibitors of mitophagy that could be combined with other drugs that induce mitochondrial dysfunction, such as respiratory inhibitors or antibiotics, to further increase the requirement for functional mitophagy.