Mitochondrial membrane lipids and respiratory efficiency

Project Summary No energy transfer processes are perfectly efficient. Mitochondrial oxidative phosphorylation (OXPHOS) consists of a sequence of reactions with known nodes of inefficient energy transfer. Exercise training is known to improve skeletal muscle mitochondrial efficiency to maximize energy output. The premise of this proposal is to examine how cardiolipin (CL) in the inner mitochondrial membrane (IMM) modulates OXPHOS efficiency to alter skeletal muscle and whole-body energy expenditure. CL is a cone-shaped non-bilayer lipid that induces membrane curvature in cristae, and binds with high affinity to mitochondrial respiratory complexes to regulate their functions. Exercise or inactivity alters muscle mitochondrial CL content, coincidental to changes in OXPHOS efficiency. Preliminary tissue-specific gain- or loss-of-function studies suggest that reduced mitochondrial CL diminishes OXPHOS efficiency to protect mice from diet-induced obesity. The central hypothesis of this proposal is that exercise promotes CL biosynthesis to improve OXPHOS energy efficiency. Combining mitochondrial diagnostics, lipidomics, and metabolic phenotyping, the role of CL in energy transduction will be examined.