Mitochondrial network responses in oxidative physiology and disease

Abstract

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.

Metabolome Wide Association Study of serum DDT and DDE in Pregnancy and Early Postpartum

“…Several long-chain fatty acid were increased and acylcarnitines were decreased in association with p,p'-DDE, but not with p,p'-DDT. This metabolic signature was consistent with pathway enrichment analysis indicating an impairment in mitochondrial energy production from fatty acids [17,[46][47][48]. Common metabolites involved in metabolic pathways of sialic acid, galactose and hexose ( Figure 3 and 4) were also found in association with p,p'-DDE and o,p'-DDT.…”

“…MWAS of p,p'-DDT and o,p'-DDT exposure in women and in mice, showed alterations to metabolic features of the urea cycle and another non-essential amino acid metabolism pathway, arginine and proline. MWAS of p,p'-DDE showed an metabolic signature that was distinct from the human DDT signatures and that of mice exposed to DDT, revealing a DDE association with numerous mitochondrial defects including disruption of carnitine shuttle, fatty acid biosynthesis and metabolism [17,[46][47][48].…”

Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling

“…Moreover, redox is a key part of immune response in both pathogen suppression and host signaling [56] , [57] . Recent studies show that combined metabolomics and transcriptomics analyses provide sensitive approaches to link oxidative stress to biologic responses [58] . Here we demonstrate that, compared to naïve subjects, those with previous history of P. vivax malaria exhibited distinct plasma metabolic signatures during a CHMI trial.…”

Physiological regulation of reactive oxygen species in organisms based on their physicochemical properties

“…In contrast, a continuous low rate of ROS generation is necessary for regulating the magnitude of the electrochemical proton gradient that is used to drive ATP synthesis . ROS compartmentalization along with the delicate antioxidant system solves the above contradiction between oxidative damage and redox signalling in the mitochondria . Moreover, ROS compartmentalization appears to be an important determinant to assure the type‐specific and stimulus‐specific effects of each oxidative signalling pathway.…”