Mitochondria are fascinating, multi-functional organelles. Besides their well-known function in energy production, they play a central role in various aspects of cellular metabolism, participate in calcium signaling, innate immunity and cell death. Mitochondrial dysfunction underlies many common and rare diseases, and proper regulation of mitochondrial functions is critical for health. Our long-term research goals are to elucidate signaling pathways that regulate mitochondrial functions and to exploit these pathways as therapeutic targets.
We are particularly interested in understanding the interplay between mitochondria and calcium signaling. Calcium is a central signaling ion, its cellular concentrations are tightly regulated. The intricate relationship between calcium and mitochondria has been appreciated for a long time: entry of calcium into the mitochondria activates energy production and mitochondrial calcium overload leads to cell death. However, the molecular machinery that mediates entry of calcium ions into the mitochondria was not known until recently, making perturbation and study of mitochondrial calcium uptake challenging. Recent characterization of the Mitochondrial Calcium Uniporter brings many opportunities to further understand the interplay between calcium and mitochondria.
1. How is mitochondrial calcium uptake regulated?
MCU is a multi-protein complex, and its activity is highly regulated. We are interested in understanding the details of this regulation
Schematic representation of the mitochondrial calcium uniporter complex (uniplex). The uniplex resides on the inner membrane of mitochondria and forms a calcium channel. Calcium entry into the mitochondria plays an important role in cellular calcium homeostasis , energy production and mitochondrial health. MCU is the pore forming subunit, calcium ions pass through it to enter the mitochondria. MICU1 and MICU2 are gatekeeper proteins that block the passage of calcium ions until cytoplasmic calcium concentration is high (above a certain threshold). MCUb is thought to be a negative regulator of mitochondrial calcium uptake. EMRE is a regulator subunit with two functions: it keeps the MCU calcium pore open, and it mediated MCU-MICU1 interaction.
2. How does mitochondrial calcium uptake affect mitochondrial functions?
Calcium ions stimulate mitochondrial energy production. We are interested in understanding how calcium ions regulate other mitochondrial functions and pathways.
3. What are the physiological consequences of perturbed mitochondrial calcium uptake?
We have generated mouse strains that lack MCU in different tissues and we are studying the effects of loss of mitochondrial calcium uptake in normal physiology.