This study investigated the relationship between mitochondrial respiratory chain capacity and stress-related behaviors in male mice. Miniaturized assays of mitochondrial enzyme activities and mtDNA content were performed on 571 samples across 17 brain areas. Multi-slice network analysis identified three large-scale networks with shared mitochondrial signatures. A cortico-striatal network showed the strongest mitochondria-behavior correlations, accounting for up to 50% of behavioral differences. The mito-based brain networks overlapped with gene expression and structural connectivity, exhibiting distinct molecular mitochondrial phenotype signatures. This research provides evidence for distinct, behaviorally-relevant mitochondrial phenotypes across the male mouse brain.

Ayelet M. Rosenberg, Manish Saggar, Anna S. Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V. Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard