Transcriptional Coordination between Mitochondrial and Nuclear Genomes for Oxidative Phosphorylation Is Disrupted in Alzheimer’s Brain

Abstract

Abstract Decline in mitochondrial function and oxidative phosphorylation in Alzheimer’s disease (AD) are well documented which led us to investigate coordination between mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genomes specific to oxidative phosphorylation (OXPHOS). Using AMP-AD mtDNA and nDNA datasets, regression analyses of OXPHOS transcriptomic, proteomic profiles and AD clinical biomarkers were conducted. Outcomes revealed that mtDNA and nDNA encoded OXPHOS subunits were negatively correlated at mRNA level while positively correlated at protein level in both cognitively normal and AD brains. However, association between mitochondrial and nuclear OXPHOS transcripts was significantly lower in AD brain. Mitochondrial transcripts were positively correlated with Notch signaling while negatively correlated with synapse formation, bioenergetics, translation, and ubiquitin-related pathways in both control and AD brain. mtDNA- transcript levels were negatively correlated with neuronal cell fractions but positively correlated with oligodendrocyte precursor cell fraction. AD biomarkers, β−amyloid, total tau, and neurofibrillary tangle (NFT) burden, were positively correlated with mtDNA transcript levels. Collectively, our findings reveal altered mitochondria-nuclear genome interactions under AD stress, uncoupled mitochondrial / nuclear genome communication in AD, key role of precursor oligodendrocytes in OXPHOS and AD and suggest coordination between mitochondrial and nuclear genomes regulating OXPHOS as a potential therapeutic target in AD.