Research

The intersection of mitochondrial function and human health

More than a powerhouse

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, and 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.

Calcium signaling is central to cellular function

We are particularly interested in understanding the interplay between mitochondria and cellular calcium signaling. Calcium is a vital signaling ion and 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 uniporter complex brings many opportunities to further understand the interplay between calcium and mitochondria.

Mitochondria help regulate calcium signaling

A key player in our research is 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.

The uniplex is composed of several proteins. MCU is the pore forming subunit and 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 exceeds 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 mediates the interaction between MCU and MICU1.

Research Topics