Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

Abstract

Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

“…46 Increasing evidence, however, supports the notion that mitophagy can also occur independently of Parkin/Pink1. [47][48][49][50][51] The initial report showing that selective mitophagy occurs in PINK1-deficient neuroblastoma cells 51 was followed by studies showing that Parkin may be recruited through PINK1-independent mechanisms both in vitro and in vivo. 52,53 Pathways independent of both PINK1 and Parkin have also emerged, often involving mitophagy stimuli that cause lesser degrees of or no mitochondrial depolarization.…”

Autophagy at the crossroads of catabolism and anabolism

“…Similarly, the phosphorylation of serine residues flanking the LIR motif of BNIP3 promotes the binding of BNIP3 to LC3B and Golgi-associated ATPase enhancer of 16 kDa (GATE16; another Atg8 orthologue), thus facilitating mitophagy 35 . By contrast, dephosphorylation of the LIR of FUNDC1 is required to promote mitophagy during hypoxia 33 .…”

“…For example, damaged and superfluous mitochondria are targeted to autophagosomes in a process termed mitophagy 24,25 . Numerous studies have led to the identification of mitophagy receptors such as Atg32 in yeast, as well as BCL2/adenovirus E1B 19 kDa proteininteracting protein 3 (BNIP3), NIP3-like protein X (NIX) and FUN14 domain-containing protein 1 (FUNDC1) in mammals [26][27][28][29][30][31][32][33] . These receptors all possess an LIR motif to directly target mitochondria to autophagosomes.…”

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

“…Furthermore, several lines of evidence demonstrate the participation of other receptors during autophagosomal recognition of mitochondria, including BNIP3L, BNIP3, and FUNDC1, hence the potential involvement of those receptors in mitophagy regulation of cigarette-induced cellular senescence need to be examined in future studies. [18][19][20][21] Programmed cell death (PCD) has been widely implicated in COPD pathogenesis and the involvement of autophagy, including mitophagy, has been reported in not only apoptosis but also programmed necrosis, necroptosis. 32,33 The central purpose of both PCD and cell senescence is eliminating damaged cells for tissue regeneration, indicating that the extent of cell damage may be critical for determination of cell fate.…”

“…16 Proteins localized on the mitochondrial outer membrane, including BNIP3L, BNIP3, and FUNDC1 (FUN14 domain containing 1), are specific receptors for mitophagic recognition during red blood cell maturation, metabolic stress, and hypoxia. [18][19][20][21] Thus far, the PINK1-PARK2 pathway has been largely implicated in the removal of damaged mitochondria with depolarized membranes. 22 Stress-induced membrane depolarization stabilizes PINK1, resulting in recruitment of PARK2, an E3-ubiquitin ligase, to mitochondria.…”