FUNDC 1 regulates mitochondrial dynamics at the ER –mitochondrial contact site under hypoxic conditions

Abstract

In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ERmitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/ calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

“…Besides, downregulation of DLP1 has been reported to prevent mitochondrial autophagy in mouse heart (Ikeda et al ., 2015; Shirakabe et al ., 2016). DLP1 has also been described to modulate mitophagy, possibly involving the interaction of DLP1 with the mitophagy receptor FUN14 domain‐containing 1 Pan troglodytes (FUNDC1) (Zuo et al ., 2014; Wu et al ., 2016). In yeast, the autophagic scaffold protein atg11p binds to and recruits Dnm1p/DLP1 to promote mitochondrial fission that occurs upon mitophagy (Mao et al ., 2013).…”

Expanding perspectives on the significance of mitophagy in cancer

“…Moreover, fission has been shown in several systems to be induced in parallel with, and to be required for mitophagy [23–25], while mitochondrial fusion can protect mitochondria against mitophagy [26,27]. A number of mitophagy regulators including BNIP3 and FUNDC1 have been localized to both the ER and mitochondria [28,29] but further work is necessary to elucidate the timing and topology of recruitment of specific mitophagy factors to these sites.…”

“…Similar to other forms of mitophagy, BNIP3-dependent mitophagy requires Drp1-induced fission; inhibition of fission or knockdown of Drp-1 blocks hypoxia-induced, BNIP3-dependent mitophagy [87]. However, BNIP3/BNIP3L dependent/hypoxia-induced mitophagy is not dependent on PINK1 or Parkin [29,88] and BNIP3 is not required for PINK1 accumulation or Parkin recruitment to the OMM although BNIP3 can compensate for PINK1 inactivation possibly by acting in parallel to induce mitophagy [88]. BNIP3L has been reported to stimulate mitophagy induced by Parkin in response to mitochondrial depolarization with CCCP [89] and to be a direct target of Parkin [90].…”

“…In response to hypoxia, FUNDC1 accumulates at mitochondrial-ER junctions where it interacts directly with processed LC3, DRP-1 and indirectly with Calnexin [29]. FUNDC1 is essential for hypoxia-induced mitophagy possibly due to its role in recruiting DRP-1 [29]. This is evidenced by inhibition of FUNDC1-induced mitophagy via expression of mutant forms that block its interaction with DRP-1.…”

Mitochatting – If only we could be a fly on the cell wall

“…The outer mitochondrial membrane protein FUNDC1 was also reported to be localized to MAMs, where it interacts with calnexin. In the MAM it is involved in hypoxia-induced mitophagy and mitochondrial fission through interaction with the fission protein DRP1 [50].…”