We investigate the pathophysiological roles of mitochondrial Ca2+ regulation.
Mitochondrial Ca2+ controls the life and death of mammalian cells. It regulates ATP output in mitochondria, and plays central roles in initiating programmed cell death. Perturbation of mitochondrial Ca2+ hemeostasis has been linked to progression of neurodegenerative diseases, such as the Alzheimer's Disease, and death of cardiac muscles during myocardial ischemia reperfusion.
We ask the following questions:
1. How do cells achieve mitochondrial Ca2+ homeostasis?
2. How does mitochondrial Ca2+ control pathophysiological processes?
3. Can we treat pathological conditions by manipulating mitochondrial Ca2+?
Our research extends from molecular to cellular levels.
Project #1: Molecular mechanisms of the mitochondrial calcium uniporter
We are currently combining membrane-protein purification, biochemical analysis, functional reconstitution, electrophsyiology, and cryo-EM to investigate how the uniporter functions as a molecular machine using the principles of physics and chemistry.
- What is the mitochondrial calcium uniporter?
The mitochondrial calcium uniporter is a multi-subunit Ca2+ ion channel complex that regulates mitochondrial Ca2+ by transporting cytoplasmic Ca2+ into mitochondria. The genes encoding uniporter subunits were discovered in 2010–2013.
- What have we achieved?
Our work identified molecular interactions that drive assembly of uniporter subunits into a complex, and determined the functional roles of these molecular contacts. Link
Patch-clamp electrophysiology has been the gold standard of ion-channel analysis, but applying this approach to the uniporter is difficult because the mitochondrial membrane is small.
We have overcome this problem by engineering uniporter proteins to travel to cell membranes. This allows us to efficiently obtain macroscopic and single-channel recordings. Link
Project #2: Cellular mechanisms to regulate mitochondrial calcium
We investigate how a network of proteins act together to achieve mitochondrial Ca2+ homeostasis, and how perturbation of their functions impact cellular physiology. Live cell imaging, induced pluripotency stem cells, and genome editing methods are combined to address our research questions.
- Recent work
Normal Mitochondria
EMRE proteolysis perturbed
We recently discovered a mammalian protease pathway, in which mitochondrial AAA proteases AFG3L2 and SPG7 use the energy of ATP hydrolysis to remove an excessive uniporter subunit in the mitochondrial inner membrane. Perturbation of this pathway leads to accumulation of a uniporter subcompelx, which constitutively loads calcium into mitochondria to induce mitochondrial permeability transition and cell death. Link