Four Opa1 isoforms are expressed in mice, which differ in the presence or absence of cleavage sites for Oma1 and for Yme1l. Mutations in the gene OPA1 (optic atrophy) cause autosomal dominant optic atrophy (ADOA) in humans, which is associated with the selective loss of retinal ganglion cells and blindness. Missense mutations in OPA1 lead to multisystem disorders with a wide range of clinical manifestations.
The gene OPA1 encodes a mitochondrial dynamin-related GTP protein and plays a crucial role in numerous mitochondrial processes, such as inner membrane fusion and cristae morphogenesis, but not much is known about the different Opa1 isoforms and the role of Opa1 processing.
In this new study a team of researchers led by the MPI for Biology of Aging in Cologne, Germany, shed light on the physiological role of Opa1 isoforms and Opa1 cleavage by investigating these processes in novel isoform specific mouse models.
To allow the analysis of Oma1-mediated Opa1 processing in vivo, a mouse model was generated by genome editing that exclusively expresses Opa1v1, harboring only the Oma1 cleavage site. While Opa1 KO in mice is lethal, Opa1v1 mice were born healthy, in expected Mendelian ratios and showed no apparent phenotype. Further no abnormalities in OXPHOS capacity of heart tissue, mitochondrial size and structure were observed. An additional mouse model harboring a non-cleavable Opa1, Opa1v1Δ4, also developed normally. The mice had a normal life span, gained body weight as WT mice, and showed no apparent phenotype. Analysis of the eye function revealed no signs of optic atrophy in either of the mouse lines. Opa1v1 or Opa1v1Δ4 mice did not exhibit the mitochondrial dysfunction typically associated with OPA1 mutations observed in human cases, indicating a lack of the characteristic mitochondrial disease manifestations. Also challenge situations as high fat diet and cold challenge revealed that balanced Opa1 processing is not essential for normal health in these mice.
Giving the fact that OXPHOS deficiency induces Opa1 processing by Oma1 in vivo, the role of Opa1 processing in cardiomyopathy associated with OXPHOS dysfunction was investigated. Opa1v1 and Opa1v1Δ4 mice were crossed with cardiac and skeletal muscle–specific knockout mice of Cox10. Loss of Opa1 processing markedly reduced the life span of Cox10−/− mice (v1Δ4), whereas the cleavable isoform (v1) preserves the life span of Cox10−/− mice, pointing to a protective role of Opa1 processing under severe OXPHOS stress in cardiomyopathy.
The new data highlights the critical regulatory role of Opa1 processing and related mitochondrial dynamics for cardiac hypertrophy and it has to be further investigated, if this holds true for diseases linked to severe OXPHOS stress.
Ahola S, Pazurek LA, Mayer F, Lampe P, Hermans S, Becker L, Amarie OV, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Riedel D, Nolte H, Langer T. Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy. Sci Adv. 2024 Aug 2;10(31):eadp0443. doi: 10.1126/sciadv.adp0443. Epub 2024 Aug 2.