title: The loss of LRPPRC function induces the mitochondrial unfolded protein response.
abstract: The inactivation of the LRPPRC gene, which has previously been associated with the neurodegenerative French Canadian Leigh Syndrome, results in a decrease in the production of mitochondria-encoded subunits of complex IV, thereby causing a reduction in complex IV activity. Previously we have shown that reducing complex IV activity triggers a compensatory and conserved mitochondrial hyperfusion response. We now demonstrate that LRPPRC knock-down in mammalian cells leads to an imbalance between mitochondria-encoded and nuclear-encoded subunits of complex IV and that this imbalance triggers the mitochondrial unfolded protein response (UPR(mt)). The inactivation of the LRPPRC-like gene mma-1 in C. elegans also induces UPR(mt), which demonstrates that this response is conserved. Furthermore, we provide evidence that mitochondrial hyperfusion and UPR(mt) are coordinated but mediated by genetically distinct pathways. We propose that in the context of LRPPRC mma-1 knock-down, mitochondrial hyperfusion helps to transiently maintain mitochondrial ATP production while UPR(mt) participates in the restoration of mitochondrial proteostasis. Mitochondrial proteostasis is not only critical in pathophysiology but also during aging, as proteotoxic stress has been shown to increase with age. Therefore, we speculate that the coordination of these two mitochondrial stress responses plays a more global role in mitochondrial proteostasis.
authors.affiliation: Center for Integrated Protein Science, Fakultät für Biologie, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Köhler
authors.affiliation: Center for Integrated Protein Science, Fakultät für Biologie, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
authors.forename: Anne Kathrin
authors.initials: AK
authors.lastname: Müller-Rischart
authors.affiliation: Center for Integrated Protein Science, Fakultät für Biologie, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Conradt
authors.affiliation: Center for Integrated Protein Science, Fakultät für Biologie, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
authors.forename: Stéphane Guy
authors.initials: SG
authors.lastname: Rolland
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; C087940:LRPPRC protein, human; C584057:MMA-1 protein, C elegans; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate
keywords: LRPPRC; UPR; mitochondrial hyperfusion; mitochondrial stress response; mma-1