POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels
Year: 2025
Type: article
Abstract: POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc , which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.
Source: Life Science Alliance
Institutions: Max Planck Institute for Biology of Ageing, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut de Biologie Intégrative de la Cellule, The Kids Research Institute Australia, Princess Margaret Hospital for Children, Perth Children's Hospital, The University of Western Australia, ARC Centre of Excellence in Synthetic Biology, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Karolinska Institutet
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: French Muscular Dystrophy Association, Agence Nationale de la Recherche, Cancerfonden, Department of Health and Aged Care, Australian Government, Knut och Alice Wallenbergs Stiftelse, Fondation ARC pour la Recherche sur le Cancer, Vetenskapsrådet, Department of Education and Training, Novo Nordisk Fonden, European Research Council
Awards: G1406548146, G1412174231, Regulation of mitochondrial function in health and disease, G272399368, Deciphering the role of the N-terminal extension of POLRMT in the regulation of mammalian mitochondrial gene expression, G3691759125, G423078012, G4294899391, G440517729, G5135895447, G5276238955, G5335184011, G5335189620, G5391477827, G6063717635, G6192871179
OpenAlex ID: W4415306436