The Nucleus/Mitochondria-Shuttling LncRNAs Function as New Epigenetic Regulators of Mitophagy in Cancer

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.

Keywords: cancer metabolism; cancer stem cells; cancer therapy; long non-coding RNA; mitochondria; mitophagy.

FIGURE 1

Major events in the field of mitophagy. The idea of mitochondrial degradation was first suggested by Lewis and Margaret in 1915. With the use of electron microscopy, the presence of mitochondria within vesicles and lysosomes in rat tissues was observed in 1957. de Duve postulated the concept of cellular autophagy in 1966. Ohsumi’s lab identified the first autophagy gene in 1993 (Tsukada and Ohsumi, 1993). In 1998, the term mitophagy was first used by Klionsky and Scott (Scott and Klionsky, 1998). BNIP3L was shown to play a vital role in mitophagy during mammalian erythrocyte differentiation in 2007 (Schweers et al., 2007). Parkin and PINK1 were characterized in 2008 (Narendra et al., 2008) and 2010 (Matsuda et al., 2010), respectively. Chen et al. discovered the mitophagy receptor FUNDC1 in 2012. Ohsumi won the Nobel Prize for his groundbreaking work in the field of autophagy in 2016. Wei et al. (2017) found the IMM protein, prohibitin 2 (PHB2), as a crucial mitophagy receptor in 2017. In 2018, Juliette et al. used a fluorescent pH-biosensor system to generate the mito-QC reporter for assessing basal mitophagy in vitro and in vivo (Lee J. J. et al., 2018). A fluorescent probe system called mt-Keima was also developed, which uses a pH-sensitive protein with a pH-dependent shift in fluorescence excitation to assess mitophagy in cells and tissues.

FIGURE 2

Major regulatory pathways of mitophagy. The schematic diagram summarizes the ubiquitin (Ub)-dependent and independent mitophagy pathways. (A) Ub-dependent mitophagy. (1) Aberrations in mitochondrial membrane potential leads to stabilization and activation of PINK1 on OMM. (2) The PINK1 kinase phosphorylates basal Ub and the cytosolic Ub ligase Parkin. Parkin is recruited to the mitochondria and activated by phospho-Ub and PINK1 phosphorylation. (3) Generation of Ub chains recruit mitophagy receptors, such as OPTN, NDP52, or p62. (4) Autophagosome machinery is recruited by mitophagy receptors. Mitophagy receptors then interact with LC3/GABARAP proteins coating the forming phagophore. (B) Ub-independent mitophagy. (1) Hypoxia stimulates HIF1α expression, and FUNDC1, NIX, and BNIP3 accumulate on the OMM and interact with LC3 to mediate mitophagy. (2) BCL2L13 interacts with LC3 proteins to mediate mitophagy (Murakawa et al., 2015).

FIGURE 3

Schematic diagram of mitophagy promoting tumor progression. In normal cells, mitophagy eliminates damaged mitochondria and protects the normal metabolism of the cells. When mitophagy is inhibited, cells are prone to carcinogenesis. In solid tumors, cancer cells face metabolic stress from limited oxygen and nutrient availability. Mitophagy removes dysfunctional mitochondria that cannot metabolically handle the nutrient stress and maintain the cancer stem cell phenotype, hence facilitating tumor progression.

FIGURE 4

Long non-coding RNAs regulate the biological behavior of tumor cells through mitophagy. LncRNA MALAT1, after being transcribed from the nuclear genome, can be aberrantly transported to the mitochondria, where it epigenetically regulates mitochondrial functions and mitophagy. Depletion of MALAT1 downregulates mitophagy markers, particularly PINK1, P62, BNIP3, NDP52, and LC3.