Mitochondrial Driving Forces and Metabolic Resilience

Abstract

Evidence supporting a causal link between mitochondrial performance and disease risk has been bolstered by the advent and application of state‐of‐the‐art multi‐omics molecular profiling technologies, such as genomics, proteomics and metabolomics. Although these are powerful tools that can produce provocative molecular signatures of disease, they still do not tell us how well (or not) mitochondria resident in specific tissues are able to maintain the free energy of ATP hydrolysis (ΔGATP, i.e. ATP:ADP ratio)–the energetic currency that powers normal cell and organ function. Thus, we came to recognize that progress toward deciphering the precise role of mitochondria in the disease process requires sophisticated approaches that can assess changes in carbon flux and bioenergetics in intact mitochondria working to regenerate ATP, and maintain ΔGATP, in the context of physiologically relevant energy demands and thermodynamic constraints (i.e. backpressure). To this end, we developed a new multiplexed assay platform for interrogating respiratory kinetics and thermodynamics under multiple substrate and energetic conditions. Unlike conventional respirometry methods, the new platform permits comprehensive assessment of respiratory fluxes (JO2) and energy transduction, which refers to the transfer of energy in carbon fuels–to electron potential energy (NAD(P)H/NAD+ redox)–to membrane potential–to ΔGATP. Importantly, these assays are performed in the context of dynamic extramitochondrial ATP:ADP concentrations (i.e. ΔGATP) that are precisely controlled within a (near) physiologic range. In simple terms, our diagnostic assays mimic an exercise “stress test” by evaluating how well a given population of mitochondria, fueled by specific mixtures of carbon substrates, responds to a graded energetic challenge. We have been combining this platform with mass spectrometry‐based metabolomics and proteomics to evaluate mitochondrial remodeling, and corresponding changes in respiratory power and efficiency, in response to a variety of nutritional and genetic maneuvers. This seminar will discuss new insights pertaining to the interplay between mitochondrial driving forces and metabolic resilience.Support or Funding InformationSupported by grants from NIDDK and NHLBI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.