Mitochondrial E3 ligase MARCH 5 regulates FUNDC 1 to fine‐tune hypoxic mitophagy

Abstract

Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate mitophagy in response to stresses, or how mitophagy receptors sense stress signals to activate mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia-induced mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia-induced mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward mitophagyinducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine-tune mitochondrial quality.

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…This process accelerates Parkin translocation from the cytosol to the mitochondria,49, 54 and thus ubiquitinates mitochondrial outer membrane proteins to promote recruitment of an autophagosome 55. Other than the PINK1/Parkin pathway, BNIP3, BNIP3L and FUNDC1 are also emerging key players in the regulation of mitophagy 13, 56, 57. A full understanding of the regulatory mechanisms involved in cardiomyocyte mitophagy has yet to be developed, as well as their connection with the onset of diabetes 13.…”

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…Under hypoxia condition, ULK1‐mediated phosphorylation at Ser17 can promote the interaction between FUNDC1 and LC3 . Additionally, the mitochondrial E3 ligase MARCH5 can regulate hypoxia‐induced mitophagy through ubiquitinating and degrading FUNDC1 . The receptor‐interacting serine/threonine‐protein kinase 3 (Ripk3) can suppress FUNDC1‐mediated mitophagy and promote mitochondrial apoptosis in cardiac ischemia/reperfusion injury .…”

“…47 Additionally, the mitochondrial E3 ligase MARCH5 can regulate hypoxia-induced mitophagy through ubiquitinating and degrading FUNDC1. 48 The receptor-interacting serine/threonine-protein kinase 3 (Ripk3) can suppress FUNDC1-mediated mitophagy and promote mitochondrial apoptosis in cardiac ischemia/reperfusion injury. 49 Unexpectedly, it is also suggested that knockdown or overexpression of FUNDC1 has insignificant influence on starvation-or hypoxia-induced mitophagy.…”

Mammalian mitophagy – from in vitro molecules to in vivo models

“…The interaction between FUNDC1 and LC3 can be further strengthened following UNC‐51‐like kinase 1 (ULK1)‐dependent phosphorylation of FUNDC1 at serine 17 . Beyond phosphorylation, ubiquitylation has also been implicated as a FUNDC1 control mechanism . The OMM‐localised E3 ligase MARCH5 can ubiquitylate FUNDC1 at the early stages of hypoxia, before FUNDC1 dephosphorylation, to prevent excessive mitophagy .…”

“…Beyond phosphorylation, ubiquitylation has also been implicated as a FUNDC1 control mechanism . The OMM‐localised E3 ligase MARCH5 can ubiquitylate FUNDC1 at the early stages of hypoxia, before FUNDC1 dephosphorylation, to prevent excessive mitophagy .…”