Abstract
Mitophagy is a specialized autophagic pathway responsible for the selective removal of damaged or dysfunctional mitochondria by targeting them to the autophagosome in order to maintain mitochondria quality. The role of mitophagy in tumorigenesis has been conflicting, with the process both supporting tumor cell survival and promoting cell death. Cancer cells may utilize the mitophagy pathway to augment their metabolic requirements and resistance to cell death, thereby leading to increased cell proliferation and invasiveness. This review highlights major regulatory pathways of mitophagy involved in cancer. In particular, we summarize recent progress regarding how nuclear-encoded long non-coding RNAs (lncRNAs) function as novel epigenetic players in the mitochondria of cancer cells, affecting the malignant behavior of tumors by regulating mitophagy. Finally, we discuss the potential application of regulating mitophagy as a new target for cancer therapy.
Highlights
Mitochondria play a central role in cellular bioenergetics, regulating essential biochemical reactions that generate adenosine triphosphate (ATP) and reactive oxygen species (ROS; Friedman and Nunnari, 2014; Spinelli and Haigis, 2018; Missiroli et al, 2020)
Mitophagy is activated by hypoxia, metabolic stress, and mitochondrial depolarization through regulatory pathways involving PINK1/Parkin, BNIP3/NIX, and FUNDC1 (Poole and Macleod, 2021)
This study proved for the first time that the long non-coding RNAs (lncRNAs) encoded by the nuclear genome might act as a new epigenetic player and regulate mitochondrial metabolism through mitophagy
Summary
Mitochondria play a central role in cellular bioenergetics, regulating essential biochemical reactions that generate adenosine triphosphate (ATP) and reactive oxygen species (ROS; Friedman and Nunnari, 2014; Spinelli and Haigis, 2018; Missiroli et al, 2020). After hypoxia or other stress stimulation, BNIP3 and NIX can form stable homodimers in the outer mitochondrial membrane and recruit LC3 to induce mitophagy (Figure 2B; Rogov et al, 2017; Marinkovicet al., 2021; Springer et al, 2021) Both pathways cooperate to ensure efficient mitophagy (Lee et al, 2011; Zhang T. et al, 2016). Depletion of Parkin or inhibition of autophagy with chloroquine reduced CD44 high-expressing cells both in vitro and in vivo These studies suggest that PINK1/Parkin-dependent mitophagy may play an essential role in promoting the development of tumors. Recent studies have shown that mitophagy plays an important role in the metabolic transition of tumors and the maintenance of phenotype of cancer stem cells (CSCs). Mitophagy may play a critical role in this reprogramming by Mitophagy pathways
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