Eukaryotic Mitogenomes and Their Key Insights: Architecture, Evolution, and Mitonuclear Coevolution

Mitochondrial genomes (mitogenomes) are no longer considered entities solely responsible for cellular bioenergetics, but as dynamic, multifaceted, and synchronized systems that integrate genome architecture, evolutionary processes, and organismal physiology. The present review summarizes the contemporary understanding of mitogenome organization and its diversity, evolution, and associated functions across eukaryotic life, with emphasis on mitonuclear co-evolution and relevance to human health. Moreover, the conserved and lineage-specific characteristics of mitogenome architecture, including its genetic content, topology, and regulatory elements, and their roles in governing the precise replication and transcription of the mitogenome are also comprehensively discussed. Additionally, the review explores the role of evolutionary dynamics, with emphasis on mutation-rate heterogeneity, recombination dynamics, gene rearrangements, and the interaction between mutation, natural selection, and genetic drift in shaping mitochondrial genome diversity and evolutionary trajectories. Comparative approaches have revealed extensive diversity in mitogenome structural organization and composition, which are closely associated with life-history traits of organisms, including metabolic rate, longevity, and reproductive characteristics. Notably, at the functional level, the variability potential of a mitogenome significantly influences oxidative phosphorylation efficiency, reactive oxygen species generation, and the orchestration of cellular signaling cascades. Fundamental to these processes is the existence of coordinated mitonuclear interrelationships, wherein coevolution between mitochondrial and nuclear-encoded genes safeguards bioenergetic functional integrity, whereas disruptions in this coordination may lead to reduced cellular fitness and progression of several diseases. Particularly in humans, mutations in mitochondrial DNA (mtDNA) and heteroplasmy significantly contribute to the development of primary mitochondrial disorders and are increasingly implicated in other complex disease etiologies, including neurodegeneration, metabolic syndromes, and cancer. The paper also summarizes the phylogenetic utility of mitogenomes in the genomic era, accentuating the need to employ integrative approaches that combine mitochondrial and nuclear data. Lastly, the role of emerging technological platforms, including long-read sequencing and multi-omics, is also discussed, since these approaches are expected to transform the current landscape of mitogenome research. Altogether, the manuscript positions mitogenomes as indispensable entities bridging the gaps between evolutionary histories, physiological functions, and personalized precision medicine.