Mitochondrial Membrane Lipids and Energy Flux through OXPHOS
Oxidative phosphorylation (OXPHOS) consists of a sequence of reactions by which energy from electron donors is transduced to a proton motive force that culminates in the synthesis of ATP. Energy flux through OXPHOS occurs in and across the inner mitochondrial membrane (IMM). Our lab is now beginning to use deep bioenergetic phenotyping using high-resolution respirometry, fluorometry, electrophysiology, and microscopy to dissect out the exact energy-transducing step that these lipids are influencing
The question is NOT whether a lipid CAN influence a respiratory complex activity or its energy-transducing process, but in identifying which of these processes matter in vivo. One can find literature on any class of major mitochondrial lipids to potentially influence a number of energy-transducing steps of OXPHOS, partly because a defect in one promotes defects in other places. For example, cardiolipin is known to bind or change activities of all respiratory complexes but we have found that cardiolipin deficiency with fatty liver disease is particularly detrimental to electron handover from coenzyme Q to complex III (Brothwell, et al., biorxiv, 2025). Bioenergetic assays help us to identify which energy-transducing step is most likely to be detrimental by having them all run in tandem. Using this approach, we have also identified that mitochondrial phosphatidyl-ethanolamine directly influence UCP1 proton conductance in brown adipocytes (Johnson et al., Science Advances, 2023). Thus, our experimental strategies on studying bioenergetics differ from traditional respirometry-only approach where we aim to dig deeper than whether oxygen consumption is elevated or reduced.
We are interested in developing new ways to characterize bioenergetics, based on specific observations that arise from our ongoing studies. One such effort is in utilizing super-resolution microscopy to study the influence of mitochondrial lipids on cristae shape/volume to affect membrane potential (Decker et al., Cell Metabolism, 2024). We also continue to expand studies on the relevance of mitochondrial lipids in different disease conditions.
In addition to our published studies in skeletal muscle, heart, adipose tissues, and liver, we have ongoing studies on chronic kidney disease to study proximal tubule mitochondria, as well as on β-cell glucose-stimulated insulin secretion. We also have efforts in discovering mitochondrial phospholipid transporters that have yet been identified, as well as human genetic diseases in which mutations in genes of mitochondrial phospholipid biosynthesis or transport have been implicated.
