Abstract
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.
Highlights
Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases
Since mitochondrial processes are important in brain tissue and their perturbation is thought to have a role in neurodegenerative diseases (NDs), we aimed to identify whether relationships between expression levels of mitochondrial- and nuclear-encoded genes are variable across brain regions, cell types and ND status
We find that central nervous system (CNS) regional cell-type composition contributes to regional variation in coexpression, reflecting functional specialisation, at synapses
Summary
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. We examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. Transcription of nuclear-encoded mitochondrial proteins occurs in the nucleus and translation is carried out by cytoplasmic ribosomes before the products are imported into mitochondria[8] Through these processes, the mitochondria are fully resourced to fulfil their numerous and integral roles in the cell
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