# Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration

## TL;DR

Accumulated mtDNA mutations in mice mainly impair NADH-linked respiration in specific tissues, despite overall mitochondrial function being mostly preserved.

## Contribution

This study identifies NADH-linked respiration as the primary functional consequence of mtDNA mutations in a mouse model.

## Key findings

- NADH-linked respiration is suppressed in several tissues of PolG Mut mice.
- Respiration routed from CII-CIII-CIV is largely preserved across tissues.
- PolG mutation decreases CI:CII respiration in cells, mitochondria, and tissue strips.

## Abstract

Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.

•Despite increased mitochondrial protein content, CI and IV are reduced in PolG mice•PolG Mut mice largely retain competent mitochondrial respiration across tissues•NADH-linked respiration is suppressed in several tissues of PolG Mut mice•PolG mutation decreased CI:CII respiration in cells, mitochondria, and tissue strips

Despite increased mitochondrial protein content, CI and IV are reduced in PolG mice

PolG Mut mice largely retain competent mitochondrial respiration across tissues

NADH-linked respiration is suppressed in several tissues of PolG Mut mice

PolG mutation decreased CI:CII respiration in cells, mitochondria, and tissue strips

Biochemistry; Genomics; Molecular biology