Mitofusins ‘bridge’ the gap between oxidative stress and mitochondrial hyperfusion

Abstract

During stress conditions, mitochondria can undergo hyperfusion to protect the cell. A recent study in EMBO reports identifies a new mechanism by which mitofusins can be activated to initiate mitochondrial fusion during oxidative stress.

The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease

“…MFN2 activity has been linked to oxidized glutathione on a molecular level, and overlapping functions of MFN2 and GDAP1 in regulating glutathione levels were suggested ( Ryan and Stojanovski, 2012 ; Shutt et al , 2012 ). Oxidized glutathione oxidizes MFN2 to form disulphide-mediated mitofusin oligomers, which increase mitochondrial fusion efficiency under redox stress conditions ( Shutt et al , 2012 ).…”

A new mitofusin topology places the redox-regulated C terminus in the mitochondrial intermembrane space

“…The cysteine residues responsible for these dynamic oligomers were located within the C-terminal domain, assumed to be a cytosol-exposed region. Oligomerization occurred in cis, before mitochondrial docking, suggesting that the generation of disulfide-induced Mfn2 oligomers may act to “prime” them to bind in trans and drive mitochondrial fusion ( Ryan and Stojanovski, 2012 ; Shutt et al, 2012 ). A confounding element of this previous work is that the cytosol is generally considered a reducing environment, making it difficult to envision how GSSG-induced redox switching may occur within a cytosolic domain.…”

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Prior to fusion, curving of the outer membranes is promoted by the hydrolysis of cardiolipin to phosphatidic acid, a process mediated by phospholipase-D . Once mitofusins are tethered, hydrolysis of GTP enables mitochondrial fusion (Ryan & Stojanovski, 2012).…”