OPA3 mutations highlight a patho-mechanism involving fission and autophagy

Identification: Maresca, Alessandra



OPA3 mutations highlight a patho-mechanism involving fission and autophagy
Alessandra Maresca1, Emanuela Scimonelli2, Valentina Del Dotto2, Claudia Zanna3, Sara Vidoni4, Guy Lenaers5, Cecile Delettre6, Valerio Carelli1,2
1IRCCS ISNB Bologna; 2DIBINEM and 3 FABIT, University of Bologna; 4Dana-Farber Cancer Institute, Boston, 5Angers University, 6INM, Montpellier
OPA3 is a nuclear encoded protein targeted to mitochondria. The OPA3 gene consists of three exons: two transcript variants (OPA3V1, OPA3V2) are produced by alternative splicing of exon 2 and exon 2b. Recessive mutations are associated with Costeff syndrome, whereas dominant mutations are found in Dominant Optic Atrophy, associated with cataract or hearing loss. Although the biological function of this protein within mitochondria is still uncovered, a role in the regulation of mitochondrial network morphology has been proposed. Moreover, it remains controversial the OPA3 mitochondrial sub-localization.
We confirmed a possible role for OPA3 in modulating mitochondrial network through overexpression and silencing experiments in HeLa cells. A concordant indication came from the analysis of mitochondrial network morphology in fibroblasts carrying the previously reported dominant mutation (p.Q105E) and recessive mutation (IVS1-1G>C) in OPA3V1. Both OPA3 mutant fibroblasts showed more elongated mitochondria compared to controls resulting from reduction of the OPA3V1 protein levels. However, we did not observe any direct interaction between OPA3 and fission regulators, nor even with fusion proteins. As a possible consequence of a defective fission, mutant fibroblasts showed significantly reduced LC3-II/LC3-I ratio with normal or slightly increased p62 levels, indicating a limitation in the autophagic process. Although we failed to detect a clear biochemical defect in mutant fibroblasts, we observed an increase in the MnSOD levels, indicative of increased oxidative stress, which might depend on the abnormal accumulation of aged mitochondria. Finally, we demonstrated that, in physiological conditions, both OPA3 variants are anchored to the mitochondrial inner membrane, exposing the N-term in the IM space and the C-term in the matrix. Overall, these two OPA3 mutations share a common pathogenic mechanism based on the reduction of OPA3V1 protein and blockade of mitochondrial fission, resembling the silencing condition in HeLa cells, possibly impairing autophagy and increasing mitochondrial oxidative stress.



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