TY - JOUR
T1 - OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution
AU - Elachouri, Ghizlane
AU - Vidoni, Sara
AU - Zanna, Claudia
AU - Pattyn, Alexandre
AU - Boukhaddaoui, Hassan
AU - Gaget, Karen
AU - Yu-Wai-Man, Patrick
AU - Gasparre, Giuseppe
AU - Sarzi, Emmanuelle
AU - Delettre, Cécile
AU - Olichon, Aurélien
AU - Loiseau, Dominique
AU - Reynier, Pascal
AU - Chinnery, Patrick F.
AU - Rotig, Agnès
AU - Carelli, Valerio
AU - Hamel, Christian P.
AU - Rugolo, Michela
AU - Lenaers, Guy
PY - 2011/1
Y1 - 2011/1
N2 - Eukaryotic cells harbor a small multiploid mitochondrial genome, organized in nucleoids spread within the mitochondrial network. Maintenance and distribution of mitochondrial DNA (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 evidence suggests that the actors of the mitochondrial network dynamics, among which is the intramitochondrial 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 exon 4b 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 10-kDa peptide generated by cleavage of the OPA1-exon4b isoform is responsible for this process and show that this peptide is embedded in the inner membrane and colocalizes and coimmunoprecipitates with nucleoid components.We propose a novel syntheticmodel inwhich a peptide, including two transmembrane domains derived from the N terminus of the OPA1-exon4b isoform in vertebrates or from its ortholog in lower eukaryotes, might contribute to nucleoid attachment to the inner mitochondrial membrane and promotes mtDNA replication and distribution. Thus, this study places OPA1 as a direct actor in the maintenance of mitochondrial genome integrity.
AB - Eukaryotic cells harbor a small multiploid mitochondrial genome, organized in nucleoids spread within the mitochondrial network. Maintenance and distribution of mitochondrial DNA (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 evidence suggests that the actors of the mitochondrial network dynamics, among which is the intramitochondrial 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 exon 4b 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 10-kDa peptide generated by cleavage of the OPA1-exon4b isoform is responsible for this process and show that this peptide is embedded in the inner membrane and colocalizes and coimmunoprecipitates with nucleoid components.We propose a novel syntheticmodel inwhich a peptide, including two transmembrane domains derived from the N terminus of the OPA1-exon4b isoform in vertebrates or from its ortholog in lower eukaryotes, might contribute to nucleoid attachment to the inner mitochondrial membrane and promotes mtDNA replication and distribution. Thus, this study places OPA1 as a direct actor in the maintenance of mitochondrial genome integrity.
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U2 - 10.1101/gr.108696.110
DO - 10.1101/gr.108696.110
M3 - Article
C2 - 20974897
AN - SCOPUS:78651480831
VL - 21
SP - 12
EP - 20
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 1
ER -