Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease

Fairbrother-Browne and collaborators analyze the relationship between nuclear and mitochondrial gene expression across the human brain and find correlation profiles that are governed by regional patterns. They show that these correlations are disrupted in neurodegenerative diseases, suggesting the relevance of mito-nuclear interactions for normal brain function. Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

Automated summary

Fairbrother-Browne and collaborators analyzed the relationship between nuclear and mitochondrial gene expression in the human brain, finding correlations governed by regional patterns that are disrupted in neurodegenerative diseases. The study shows that interactions between mitochondrial and nuclear genes are vital for normal brain function, and disruptions in these relationships may contribute to the pathogenesis of diseases like AD. The research presents a tool called MitoNuclearCOEXPlorer to explore crucial mitochondria-nuclear relationships in multi-dimensional brain data.