Garbincius Laboratory - Research Areas

The long-term focus of our research is to understand how striated muscle cells couple changes in energetic demand to changes in mitochondrial energy metabolism, and how disruption of this process contributes to disease. We investigate these questions across multiple levels of biological organization, from molecular studies and in vitro cellular physiology, up to in vivo assessment of whole-organ and whole-animal function.

Novel players in mitochondrial calcium exchange

The balance between mitochondrial calcium uptake and efflux has emerged as a critical signal that governs mitochondrial energetics, signaling, and cell death. We previously demonstrated a causal role for increased mitochondrial calcium accumulation in pathological cardiac hypertrophy and non-ischemic heart failure. Growing evidence also implicates altered mitochondrial calcium homeostasis in numerous other pathologies including ischemia-reperfusion injury, muscular dystrophies, neurodegeneration, and cancer. We aim to understand the regulatory mechanisms that control mitochondrial calcium efflux and how they can be targeted for the treatment of disease.

Dysregulation of cellular bioenergetics in heart failure

The healthy heart turns over its ATP supply every several seconds and consumes 15-20x its own mass in ATP each day. Cardiac muscle is critically reliant on mitochondrial oxidative phosphorylation to meet this high ATP demand and fuel contraction. However, the rate at which mitochondria can replenish ATP is commonly impaired in heart failure, reducing myocardial ATP content by up to 30%. This energy deficit limits the overall work rate and cardiac output the heart can achieve. We are investigating the mechanistic links between changes in the mitochondrial proteome and impaired oxidative metabolism in the failing heart, with a focus on novel pathways governing cardiac nucleotide metabolism.

Elucidating the 'dark' mitochondrial proteome

Mitochondrial DNA contains 37 genes that encode for 22 transfer RNAs, 2 ribosomal RNAs, and 13 mitochondrial proteins. The remainder of the ~1600 proteins that localize to the mitochondria are encoded in the nuclear genome. The function and biological significance of ~250 of these mitochondrial proteins remain virtually unknown. We are conducting unbiased functional screening for these proteins to understand their influence on mitochondrial bioenergetics and their ultimate relevance in heart failure and skeletal muscle disease. Our goal is to identify new targets for therapeutic intervention in these conditions.