Brain mitochondrial diversity and network organization predict anxiety-like behavior in mice

Abstract

The brain and behavior are under energetic constraints, which are likely driven by mitochondrial energy production capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examine the association between mitochondrial health index and stress-related behaviors in mice with diverse mitochondrial and behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain function and mitochondrial DNA (mtDNA) content were deployed on 571 samples from 17 brain regions. We find specific patterns of mito-behavior associations that vary across brain regions and behaviors. Furthermore, multi-slice network analysis applied to our brain-wide mitochondrial dataset identified three large-scale networks of brain regions. A major network composed of cortico-striatal regions exhibits highest mitochondria-behavior correlations, suggesting that this mito-based network is functionally significant. Mito-based networks can also be recapitulated using correlated gene expression and structural connectome data, thereby providing convergent multimodal evidence of mitochondrial functional organization anchored in gene, brain and behavior.

Psychosocial experiences are associated with human brain mitochondrial biology

“…S8). This suggests two things: first, that our findings partially generalize in a larger, heterogenous sample; and second, in keeping with the multifaceted nature of mitochondria and multi-protein nature of OxPhos complexes (50), that the mitochondrial indices built from comprehensive sets of proteins (in the TMT DLPFC dataset, Fig. 1) covering >90% of OxPhos proteins might be required to sensitively detect mitochondrial psychobiological associations.…”

“…Thus, while not a straightforward validation of our findings in the ROSMAP cohort, the directionality of findings aligns for related but different MitoPathways. Together with other work showing mitochondrial variations across mouse brain areas (50), this calls for future studies assessing mitochondrial psychobiological associations across different brain regions.…”

“…Alteration in mitochondrial OxPhos in defined brain regions (nucleus accumbens, prefrontal cortex) influences social behavior as well as anxiety-like and depression-like behaviors ((27, 43–48), reviewed in (49)). In syngenic animals (with the same genome), we also found that differences in mitochondrial energy production capacity in brain tissue accounted for a large fraction (20-45%) of animal-to-animal differences on anxiety-like behaviors and social interaction/avoidance (50). In humans, psychopathology, autism, and/or neurodegeneration are also related to alterations in brain mitochondrial OxPhos components and mtDNA (e.g.…”

“…(24,45,48)). Social dominance, depressive, and anxiety-related behaviors have been associated with variation in mitochondrial OxPhos capacity (43)(44)(45)(46)50). In the human brain, post-mortem studies show reduced complex I activity in relation to depression (see (52) for a review), and individuals with mitochondrial DNA defects leading to reduced OxPhos capacity exhibit a higher incidence of depressive symptoms compared to the general population (84).…”

Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures

“…Integrating individually measured metrics into latent constructs also has the added advantage of triangulating measurement error, thus yielding more stable quantitative estimates of mitochondrial content and RC function. Three recent lines of evidence, chronic life stress in human PBMCs 10 , ovarian tumor inflammation 48 , and mouse behavior 49 , found more robust associations using MHI than individual metrics of content and RC function, suggesting that MHI is a functionally-relevant metric of mitochondrial biology. Furthermore, the resulting index is also directly interpretable since an MHI value of 100 represents the average RC activity per mitochondrion in the dataset.…”