OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L

By Zhiyin Song, Hsiuchen Chen, Maja Fiket, C. Alexander, D. C. Chan. Journal of Cell Biology, 2007

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OPA1, a dynamin-related guanosine triphosphatase mutated in dominant optic atrophy, is required for the fusion of mitochondria. Proteolytic cleavage by the mitochondrial processing peptidase generates long isoforms from eight messenger RNA (mRNA) splice forms, whereas further cleavages at protease sites S1 and S2 generate short forms. Using OPA1-null cells, we developed a cellular system to study how individual OPA1 splice forms function in mitochondrial fusion. Only mRNA splice forms that generate a long isoform in addition to one or more short isoforms support substantial mitochondrial fusion activity. On their own, long and short OPA1 isoforms have little activity, but, when coexpressed, they functionally complement each other. Loss of mitochondrial membrane potential destabilizes the long isoforms and enhances the cleavage of OPA1 at S1 but not S2. Cleavage at S2 is regulated by the i-AAA protease Yme1L. Our results suggest that mammalian cells have multiple pathways to control mitochondrial fusion through regulation of the spectrum of OPA1 isoforms.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/be905cb874803a923a042e06e24c3add5a504dd2

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Citations in the corpus

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy (2008, background): “Recently, a protonophore-induced complete collapse of Dcm of the entire cell mitochondria was shown to trigger proteolytic cleavage or degradation of OPA1 long (l-)isoforms (Griparic et al, 2004; Duvezin-Caubet et al, 2006; Ishihara et al, 2006; Song et al, 2007).”
Mechanisms of mitochondrial fission and fusion. (2013, background): “Those with S2 or S3 sites are constitutively cleaved by the large intermembrane space AAA-protease Yme1L (Griparic et al. 2007; Song et al. 2007).”
Mitochondrial dynamics and apoptosis. (2008, background): “2006), and Yme1 (Griparic et al. 2007; Song et al. 2007) have been implicated in OPA1 processing.”
Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy (2011, background): “As reported previously, the long isoform of Opa1 is degraded in response to CCCP treatment (22,23), but in a Parkin-independent manner.”
The role of mitochondria in apoptosis. (2008, methodology): “Opa1 Parl Proteolytic processing (9) Paraplegin Proteolytic processing (111) Yme1L Proteolytic processing (112)”
Making heads or tails of phospholipids in mitochondria (2011, background): “In the inner membrane, OPA1 (or Mgm1 in yeast) is proteolytically processed, resulting in the balanced accumulation of long and short protein isoforms within mitochondria, both of which are required for mitochondrial fusion and cristae morphogenesis (Herlan et al., 2003; Ishihara et al., 2003; Song ”
Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure (2013, background): “…of chemical uncouplers (i.e., FCCP or CCCP) causes complete mitochondrial network fragmentation, Drp1 recruitment to the outer membrane, and OPA1 degradation (Duvezin-Caubet et al., 2006; Griparic et al., 2007; Ishihara et al., 2006; Song et al., 2007; Legros et al., 2002; Cereghetti et al., 2008).”
SLP‐2 is required for stress‐induced mitochondrial hyperfusion (2009, neutral): “Mfn1 (cid:2) / (cid:2) , Mfn2 (cid:2) / (cid:2) , Mfn1/2 (cid:2) / (cid:2) , and Opa1 (cid:2) / (cid:2) were generated as described (Chen et al , 2005; Song et al , 2007).”
The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “In mammalian cells, the long isoforms (high molecular weight) of Opa1 undergo cleavage (or degradation) when depolarization is induced or ATP is depleted (25, 32, 40, 57, 101).”