Tissue specific differences in mitochondrial DNA maintenance and expression

Abstract

The different cell types of multicellular organisms have specialized physiological requirements, affecting also their mitochondrial energy production and metabolism. The genome of mitochondria is essential for mitochondrial oxidative phosphorylation (OXHPOS) and thus plays a central role in many human mitochondrial pathologies. Disorders affecting mitochondrial DNA (mtDNA) maintenance are typically resulting in a tissue-specific pattern of mtDNA deletions and rearrangements. Despite this role in disease as well as a biomarker of mitochondrial biogenesis, the tissue-specific parameters of mitochondrial DNA maintenance have been virtually unexplored. In the presented study, we investigated mtDNA replication, topology, gene expression and damage in six different tissues of adult mice and sought to correlate these with the levels of known protein factors involved in mtDNA replication and transcription. Our results show that while liver and kidney cells replicate their mtDNA using the asynchronous mechanism known from cultured cells, tissues with high OXPHOS activity, such as heart, brain, skeletal muscle and brown fat, employ a strand-coupled replication mode, combined with increased levels of recombination. The strand-coupled replication mode correlated also with mtDNA damage levels, indicating that the replication mechanism represents a tissue-specific strategy to deal with intrinsic oxidative stress. While the preferred replication mode did not correlate with mtDNA transcription or the levels of most known mtDNA maintenance proteins, mtSSB was most abundant in tissues using strand-asynchronous mechanism. Although mitochondrial transcripts were most abundant in tissues with high metabolic rate, the mtDNA copy number per tissue mass was remarkably similar in all tissues. We propose that the tissue-specific features of mtDNA maintenance are primarily driven by the intrinsic reactive oxygen species exposure, mediated by DNA repair factors, whose identity remains to be elucidated.

Keywords: Mitochondrial DNA; mtDNA maintenance; mtDNA recombination; mtDNA replication.