Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

Abstract

The mitochondrial outer membrane protein Mitochondrial Fission Factor (Mff) plays a key role in both physiological and pathological fission. It is well established that in stressed or functionally impaired mitochondria the PINK1 recruits the ubiquitin ligase Parkin which ubiquitinates Mff to facilitate the removal of defective mitochondria and maintain the integrity mitochondrial network. Here we show that, in addition to this clearance pathway, Parkin also ubiquitinates Mff in a PINK1-dependent manner under basal, non-stressed conditions to regulate constitutive Mff turnover. We further show that removing Parkin with shRNA knockdown does not completely prevent Mff ubiquitination under these conditions indicating that at least one other ubiquitin ligase contributes to Mff proteostasis. These data demonstrate that Parkin plays a role in physiological maintenance of mitochondrial membrane protein composition in healthy mitochondria through constitutive low-level activation.

Mitochondrial fusion‐ and fission‐related protein expression in the regulation of skeletal muscle mass

“…Interestingly, the level of Mff, localized in the mitochondrial outer membrane, decreased in skeletal muscle following 14 days of overload. Lee et al (2019) demonstrated that Mff was ubiquitinated by Parkin; we also confirmed that the expression level of Parkin decreased in the hypertrophied plantaris muscle. This suggests that hypertrophic stimulation promotes the ubiquitination of Mff for turnover by Parkin.…”

Mechanisms and roles of mitochondrial localisation and dynamics in neuronal function

“…Parkin-mediated MFF ubiquitination in response to mitochondrial depolarisation recruits the autophagy adaptor p62, which subsequently facilitates the clearance of damaged mitochondria [ 174 ]. Parkin is responsible for a significant amount of MFF ubiquitination, regulating its constitutive turnover [ 175 ]; however, there is evidence that at least one other ubiquitin ligase targets MFF [ 175 ]. Similar to Mfn1, MFF is also poly-ubiquitinated by atypical chains [ 175 ], indicative of a non-degradative function.…”

“…Parkin is responsible for a significant amount of MFF ubiquitination, regulating its constitutive turnover [ 175 ]; however, there is evidence that at least one other ubiquitin ligase targets MFF [ 175 ]. Similar to Mfn1, MFF is also poly-ubiquitinated by atypical chains [ 175 ], indicative of a non-degradative function. However, the function of these atypical chains remains to be investigated.…”

“…However, this model has recently been challenged by a study in Drosophila , which found no role of STING in PD [ 246 ]. As previously mentioned, Mfn1/2 and MFF are targets of parkin-mediated ubiquitination and required for mitophagy [ 107–109 , 174 ], but interestingly, parkin conjugates atypical poly-ubiquitin chains to Mfn1 [ 113 ] and MFF [ 175 ]. Whether these modifications have a role in this pathway, and whether they could be targeted therapeutically, offers an exciting new area of research.…”