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

## TL;DR

Overexpression of POLRMT boosts mitochondrial DNA transcription initiation and exercise capacity in mice without affecting mature RNA levels.

## Contribution

The study reveals that POLRMT overexpression enhances mtDNA transcription initiation without altering mature RNA levels or causing pathology.

## Key findings

- POLRMT overexpression increases mtDNA transcription initiation and 7S RNA levels.
- Steady-state levels of mature mitochondrial RNAs remain unaffected by elevated POLRMT.
- Combined overexpression of POLRMT and Lrpprc does not increase mitochondrial transcript levels.

## Abstract

This study investigates effects of increased POLRMT levels and reports stimulation of mtDNA transcription initiation and enhanced exercise capacity without an effect on steady-state mRNA levels.

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.