bims-mitran 2025-10-19 papers

Issue of 2025–10–19
two papers selected by
Andreas Kohler, Umeå University

Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):

POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.

Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.

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.

DOI: https://doi.org/10.26508/lsa.202302563

Biochem Soc Trans. 2025 Oct 16. pii: BST20253089. [Epub ahead of print]

FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.

Justin Van Riper, Bridget J Corsaro, Monica C Pillon.

Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3'-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling oxidative phosphorylation. However, until recently, the molecular mechanisms governing their RNA metabolic activities have remained elusive. New biochemical and structural advances have provided molecular insights into the architecture and regulation of FASTK proteins. Here, we summarize the current understanding of the FASTK family's specialized roles in gene regulation, with an emphasis on mitochondrial mRNA metabolism by the proteins FASTK, FASTK domain-containing protein 4 (FASTKD4), and FASTKD5. Additionally, we leverage recent experimental structures and artificial intelligence-based prediction models to explore the molecular organization of FASTK proteins and highlight the family's signature C-terminus, a region essential for their RNA-binding activity.

Keywords: FASTK; RAP domain; RNA; gene regulation; helix-turn-helix; mitochondria; nuclease

DOI: https://doi.org/10.1042/BST20253089