Our Research Focus

 

Mitochondrial matrix calcium (Ca2+) is a double-edged sword known to regulate energy production and cell death. Ca2+ uptake into the mitochondria is facilitated by the Mitochondrial Calcium Uniporter (MCU) and driven by the large electrochemical gradient across the inner mitochondrial membrane (Δψm). Considering the Nernst equation and assuming a Δψm of −180 mV, mitochondrial matrix Ca2+ concentration would reach ~100 mM for a cytosolic calcium concentration of ~100 nM to achieve thermodynamic equilibrium. However, this concentration is never reached as a suite of proteins, ions, and reactive oxygen species tightly regulates the MCU. At the Santhanam Lab, we actively understand how divalent cations, particularly Mg2+, regulate the MCU channel. Our work is ongoing to understand Mg2+-dependent MCU regulation in physiology and disease states.

 

 

Though mitochondrial Ca2+ is known to activate critical dehydrogenases in the mitochondrial matrix, Ca2+ overload is known to trigger the opening of the permeability transition pore (PTP). PTP enables free passage of any solute molecules < 1.5 kDa. This results in osmotic imbalance, matrix swelling, uncoupling of oxidative phosphorylation, ATP depletion, and necrotic cell death. PTP opening is widely recognized as a significant cause of cell death in various conditions, including reperfusion injury, neuronal excitotoxicity, stroke, etc. Divalent cations like magnesium are known to regulate PTP. Our laboratory focus on how modulating the mitochondrial matrix Mg2+ concentration modulates PTP opening using in vivo genetically modified mouse models. Using a CRISPR/Cas9 strategy, we developed an animal model that lacks mitochondrial ion channels, specifically in the liver and heart, and studied the role of Mg2+ in modulating the PTP opening.

 

Other projects: Stay tuned for updates!