Biological Consequences of Reduced Energy Flux and Inefficient Energy Generation

Energy transfer processes are never perfectly efficient. Funai and colleagues have discovered that the degree of inefficiency in cellular energy exchange, particularly during oxidative phosphorylation, has important biological implications. Continue reading → Biological Consequences of Reduced Energy Flux and Inefficient Energy Generation

Research Statement

Lipids are the most abundant organic constituents in many humans. The rise in obesity prevalence has prompted a need for a more refined understanding of the effects of lipid molecules on cell physiology. Aberrant mitochondrial homeostasis driven by lipid infiltration may contribute to the development of metabolic disease.

Energy transduction of ETS can be compartmentalized into four distinct nodes: 1) electrons donated from NADH and succinate to complex I & II, 2) electrons transferred to complex III & IV while protons are pumped into the intermembrane space (IMS), 3) establishment of the proton motive force across the IMM, and 4) proton current flux through complex V to drive ATP resynthesis. Dogma states that steps 1 and 4 are stoichiometrically fixed, while efficiency for step 2 and 3 can be modulated. At step 2, electrons can prematurely “leak” to molecular O2 prior to complex IV. This process can be quantified by measuring JH2O2/JO2 (electron leak as percent of O2 flux) or with ΔΨm/JNADH (proton gradient generated per NADH consumed). At step 3, proton current flux can proceed independent of complex V (commonly referred to as “proton leak”), estimated by complex V-independent JO2, or with JATP/JO2 (i.e., P/O).

In states of high energy flux, supercomplex assembly of the electron transport system facilitates efficient energy transfer to maximize energy output. In states of low energy flux, reduced cellular work displaces the need for efficient energy transduction, thereby increasing electron leak and oxidative stress. We hypothesize that changes in the inner mitochondrial membrane lipid composition represents a fundamental mechanism by which efficiency for oxidative phosphorylation becomes modulated to alter susceptibility for metabolic disease. We utilize loss- or gain-of-function cell culture and mouse systems to systematically evaluate physiological consequences of altered mitochondrial lipids in a tissue-specific fashion.