Mitochondrial network responses in oxidative physiology and disease

Mitochondrial activities are linked directly or indirectly to all cellular functions in aerobic eukaryotes. Omics methods enable new approaches to study functional organization of mitochondria and their adaptive and maladaptive network responses to bioenergetic fuels, physiologic demands, environmental challenges and aging. In this review, we consider mitochondria collectively within a multicellular organism as a macroscale "mitochondriome", functioning to organize bioenergetics and metabolism as an organism utilizes environmental resources and protects against environmental threats. We address complexities of knowledgebase-driven functional mapping of mitochondrial systems and then consider data-driven network mapping using omics methods. Transcriptome-metabolome-wide association study (TMWAS) shows connectivity and organization of nuclear transcription with mitochondrial transport systems in cellular responses to mitochondria-mediated toxicity. Integration of redox and respiratory measures with TMWAS shows central redox hubs separating systems linked to oxygen consumption rate and H₂O₂ production. Combined redox proteomics, metabolomics and transcriptomics further shows that physiologic network structures can be visualized separately from toxicologic networks. These data-driven integrated omics methods create new opportunities for mitochondrial systems biology.