Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms

Area of Science:

• Mitochondrial biology
• Systems biology
• Human physiology

Background:

• Mitochondrial oxidative phosphorylation (OxPhos) capacity is generally considered a coherent individual trait.
• This implies consistent high or low OxPhos capacity across all organ systems for individuals.
• This study challenges this long-held assumption.

Purpose of the Study:

• To investigate the coherence of mitochondrial OxPhos capacity across multiple tissues in mice and humans.
• To explore the molecular mechanisms driving tissue-specific mitochondrial gene expression.
• To identify if distinct mitochondrial distribution patterns correlate with clinical phenotypes.

Main Methods:

• Multi-tissue molecular and enzymatic assays in mice.
• RNA sequencing (RNAseq) analysis of mitochondrial gene expression across 45 human tissues (GTEx dataset).
• Analysis of mitochondrial DNA (mtDNA) copy number (mtDNAcn) and energy sensing pathways (PGC-1α, ISR).

Main Results:

• Mitochondrial OxPhos capacity and mtDNA density showed poor correlation between tissues in mice.
• Mitochondrial gene expression coherence was limited across human tissues, with some exceptions (e.g., brain regions).
• Tissue-specific differences in mitochondrial gene expression are linked to energy sensing pathways and proliferative activity.
• Distinct subgroups of individuals with unique mitochondrial distribution strategies were identified, correlating with clinical phenotypes.

Conclusions:

• Mitochondrial OxPhos capacity is not a globally coherent trait across tissues.
• Tissue-specific regulation of mitochondrial biology, influenced by pathways like PGC-1α and ISR, drives varied mitochondrial distribution.
• Individual mitochondrial distribution strategies may contribute to unique clinical profiles.