OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions

Summary: OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1−/− MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology. Long forms supported mitochondrial fusion; short forms were better able to restore energetic efficiency. The complete rescue of mitochondrial network morphology required a balance of long and short forms of at least two isoforms, as shown by combinatorial isoform silencing and co-expression experiments. Thus, multiple OPA1 isoforms are required for mitochondrial dynamics, while any single isoform can support all other functions. These findings will be useful in designing gene therapies for patients with OPA1 haploinsufficiency. : Del Dotto et al. perform a systematic analysis of the function of each of the eight OPA1 isoforms. They find that any OPA1 isoform can rescue mtDNA content, cristae structure, and mitochondrial energetics. A specific combination of long and short forms is required for mitochondrial dynamics and network morphology. Keywords: dominant optic atrophy, mitochondrial network dynamics, mtDNA, OPA1 isoforms, OPA1 long-short form balance