Tsai Lab

Membrane-Transport Mechanisms and Molecular Physiology

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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?
Screen Shot 2018-08-16 at 12.44.19 PM

Our work identified molecular interactions that drive assembly of uniporter subunits into a complex, and determined the functional roles of these molecular contacts. 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: 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
image description

Normal Mitochondria 

Fig 12

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

Lab News

Nov 2, 2020
Anna reached an important milestone in her PhD study: first lead-author paper accepted (Cell Reports) “Mechanisms of EMRE-dependent opening in the mitochondrial calcium uniporter complex.”

May 20, 2020
New paper published in Nature.
“Structure and mechanisms of the mitochondrial calcium uniporter holocomplex.”
https://rdcu.be/b4iEz

June 15, 2019
Maddy joined the lab.

Jan 7, 2019
New paper accepted in eLife.
“The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex.” Link

Jan 2, 2019
Our lab in the University of Colorado officially opens! Anna joined the lab.

Aug 29, 2018
The lab obtained the first R01 support!
R01-GM129345

Contact

  • ming-feng.tsai@ucdenver.edu
  • 303-724-4106
  • Room 7105, Research Complex 1-North
    12800 E 19th St., Aurora, CO 80045
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