OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution
- Ghizlane Elachouri1,
- Sara Vidoni2,
- Claudia Zanna2,
- Alexandre Pattyn1,
- Hassan Boukhaddaoui1,
- Karen Gaget1,
- Patrick Yu-Wai-Man3,
- Giuseppe Gasparre4,
- Emmanuelle Sarzi5,
- Cécile Delettre1,
- Aurélien Olichon6,
- Dominique Loiseau7,
- Pascal Reynier8,
- Patrick F Chinnery3,
- Agnès Rotig5,
- Valerio Carelli2,
- Christian P Hamel1,
- Michela Rugolo2 and
- Guy Lenaers9,10
- 1 Inserm U583;
- 2 Università di Bologna;
- 3 Newcastle University;
- 4 Università di Bari;
- 5 Inserm U781;
- 6 Inserm U563;
- 7 Inserm U694;
- 8 Inserm U693;
- 9 Institut des Neurosciences de Montpellier
- * Corresponding author; email: guy.lenaers{at}inserm.fr
Abstract
Eukaryotic cells harbour a small multiploid mitochondrial genome (mtDNA), organized in nucleoids spread within the mitochondrial network. Maintenance and distribution of mtDNA are essential for energy metabolism, mitochondrial lineage in primordial germ cells, and to prevent mtDNA instability, which leads to many debilitating human diseases. Mounting evidences suggest that the actors of the mitochondrial network dynamics, among which the intra mitochondrial dynamin OPA1, might be involved in these processes. Here, using siRNAs specific to OPA1 alternate spliced exons, we evidenced that silencing of the OPA1 variants including exon4b leads to mtDNA depletion, secondary to inhibition of mtDNA replication, and to marked alteration of mtDNA distribution in nucleoid and nucleoid distribution throughout the mitochondrial network. We demonstrate that a small hydrophobic 10kDa peptide generated by the cleavage of OPA1-exon4b isoform is responsible for this process, and show that this peptide is embedded in the inner membrane and co-localises and co-immunoprecipitates with nucleoid components. We propose a novel synthetic model in which a peptide, including two trans-membrane domains derived from the amino terminus of OPA1-exon4b isoform in vertebrates, or from its orthologue in lower eukaryotes, might contribute to nucleoid attachment to the inner mitochondrial membrane, and promotes mtDNA replication and distribution. Thus, this work places OPA1 as a direct actor of the maintenance of mitochondrial genome integrity.
- Received April 3, 2010.
- Accepted October 12, 2010.
- Copyright © 2010, Cold Spring Harbor Laboratory Press
