Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes

Abstract

Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA) and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic co-regulation is poorly understood. To address this question, we analyzed ~8,500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity and morphology, we found overall positive mtDNA-nDNA OXPHOS genes' co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression was identified in the hypothalamus, basal ganglia and amygdala (sub-cortical brain regions, collectively termed the 'primitive' brain). Single cell RNA-seq analysis of mouse and human brains, revealed that this phenomenon is evolutionarily conserved, and both associate with brain cell types (involving excitatory/inhibitory neurons and non-neuronal cells) and by their spatial brain location. As the 'primitive' brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring towards glycolysis. Accordingly, we found 'primitive' brain-specific upregulation of lactate dehydrogenase B (LDHB), which associates with high OXPHOS activity, on the expense of LDHA, which promotes glycolysis. Analyses of co-expression, DNase-seq and ChIP-seq experiments revealed candidate RNA-binding genes and CEBPB as best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue dependent splice variants and OXPHOS subunit paralogs, and offered revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities.