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Updated 06/30/2020

We investigate the molecular mechanisms and pathophysiological roles of mitochondrial Ca2+ transport and homeostasis.

Mitochondrial Ca2+ controls the life and death of mammalian cells. It regulates intracellular Ca2+ signals, ATP output in mitochondria, and plays central roles in 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 membrane proteins control mitochondrial Ca2+ homeostasis?
2. How does mitochondrial Ca2+ regulate pathophysiological processes?
3. Can we treat pathological conditions by manipulating mitochondrial Ca2+ transport?

Our research extends from molecular to cellular levels.
Project #1: Molecular mechanisms of the mitochondrial calcium uniporter
The uniporter is a multi-subunit Ca2+ channel complex that imports cytoplasmic Ca2+ into the mitochondrial matrix. We combine membrane-protein purification, biochemical analyses, functional reconstitution, electrophsyiology, and structural biology to investigate how the uniporter operates as a molecular machine using the principles of physics and chemistry.

Our achievements

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We identified the molecular interactions that drive the assembly of uniporter subunits into a complex, and determined the functional roles of these molecular contacts. Link

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A structural-functional studies with our collaborators in Stanford produced a molecular model that explains how intracellular Ca2+ signals can control the opening and closing of the uniporter. Link

Fig 9L

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: The roles of mitochondrial Ca2+ in cellular physiology
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, animal models, and CRISPR genome editing methods are combined to address our research questions. 

Recent work

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Normal Mitochondria 

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EMRE proteolysis
perturbed

Fig 12 2

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