Evolutionary genomics analysis of human nucleus-encoded mitochondrial genes: implications for the roles of energy production and metabolic pathways in the pathogenesis and pathophysiology of demyelinating diseases

Abstract

The myelin sheath is a plasma membrane extension that lines nerve fibers to protect, support and insulate neurons. The myelination of axons in vertebrates enables fast, saltatory impulse propagation, and this process relies on organelles, especially on mitochondria to supply energy. Approximately 99% of mitochondrial proteins are encoded in the nucleus. Since mitochondria play a central role in the energy production and metabolic pathways, which are essential for myelinogenesis, studying these nucleus-encoded genes (nMGs) may provide new insights into the roles of energy metabolism in demyelinating diseases. In this work, a multiomics-based approach was employed to 1) construct a 1,740 human nMG subset with mitochondrial localization evidence obtained from the Integrated Mitochondrial Protein Index (IMPI) and MitoCarta databases, 2) conduct an evolutionary genomics analysis across mouse, rat, monkey, chimp, and human models, 3) examine dysmyelination phenotype-related genes (nMG subset genes with oligodendrocyte- ​and myelin-related ​phenotypes, OMP-nMGs) in MGI mouse lines and human patients, 4) determine the expression discrepancy of OMP-nMGs in brain tissues of cuprizone-treated mice, multiple sclerosis patients, and normal controls, and 5) conduct literature data mining to explore OMP-nMG-associated disease impacts. By contrasting OMP-nMGs with other genes, OMP-nMGs were found to be more ubiquitously expressed (59.1% vs. 16.1%), disease-associated (67.3% vs. 20.2%), and evolutionarily conserved within the human populations. Our multiomics-based analysis identified 110 OMP-nMGs implicated in energy production and lipid and glycan biosynthesis in the pathogenesis and pathophysiology of demyelinating disorders. Future targeted characterization of OMP-nMGs in abnormal myelination conditions may allow the discovery of novel nMG mediated mechanisms underlying myelinogenesis and related diseases.