Mitochondrial- and nuclear genome-controlled bioenergetic gene expression in Alzheimer's disease.

Abstract

Mitochondrial dysfunction is a hallmark of brain aging and particularly accentuated in neurodegenerative diseases including Alzheimer's disease (AD), yet the regulation of mitochondrial DNA (mtDNA) versus nuclear DNA (nDNA)-encoded genes in the aging- and AD brains is largely unknown. Transcriptome datasets (ROSMAP, Mayo, and MSBB) and proteome dataset (ROSMAP) from cognitively normal and AD brains were analyzed. Linear regression models were applied to evaluate the association between mtDNA-encoded and nDNA-encoded genes at transcript and protein levels. Further, pathway analysis was performed to identify biological processes correlated with mtDNA-encoded gene expression. At transcript level, mtDNA encoded genes were uniformly regulated (average R2 ranging from 0.43 to 0.92) across all datasets analyzed. While mtDNA encoded and nDNA encoded oxidative phosphorylation (OXPHOS) genes were positively correlated at protein level, they were differentially regulated at transcript level. Compared to control brains, both genesets were downregulated in AD brains at protein level whereas at the transcript level, mtDNA transcript number was higher vs nDNA transcript number was lower. In addition, transcriptional correlations between nDNA OXPHOS genes and mtDNA genes were reduced in AD brains. In both normal and AD brains, mtDNA transcripts were consistently correlated with Alzheimer's related pathways, including a positive correlation with notch signaling module and negative correlations with synapse, mitochondrial, translation, and ubiquitin mediated protein clearance modules. Across brain cell types, neuronal cell markers were negatively correlated with mtDNA transcripts whereas markers for oligodendrocyte, astrocyte and endothelial cells exhibited positive correlations. Outcomes of these analyses suggest an underappreciated correlation between mitochondrial gene expression with the development of AD, in particular the coordinated transcriptional regulation across both the mitochondrial- and nuclear genomes. While mitochondria are a promising therapeutic target for Alzheimer's disease, the findings reported herein indicate that restoring optimal mitochondrial function to prevent or treat Alzheimer's remains a complex challenge. This work was supported by National Institute on Aging grants P01-AG026572, R01 AG057931, and R01 AG059093 to RDB.