Regulation of the mitochondrial calcium uniporter

PROJECT SUMMARY
Calcium influx into the mitochondria can potently stimulate ATP synthesis, but excessive levels cause
mitochondrial failure and cell death. Such calcium overload is a prominent pathological pathway in disease
in multiple organ systems. In the heart, this phenomenon is noted during heart attacks, when prolonged
ischemia causes calcium to accumulate in the cytoplasm and subsequently overload mitochondria. In heart
failure, mitochondrial are also more susceptible to calcium overload. Calcium enters the mitochondria
through a multi-subunit calcium-activated channel known as the mitochondrial calcium uniporter. In animal
models, genetic inhibition of the uniporter has appeared protective in acute disease. In chronic diseases,
though inhibition of calcium overload is protective, there may also be basal requirements for milder
mitochondrial calcium uptake. Currently, however, there are no specific therapies to prevent calcium
overload or its downstream affects. Pharmacological modulation of the uniporter in vivo is limited by agents
that are poorly selective, cell impermeable, or produce off-target effects. A critical gap in the ability to better
modulate the uniporter is our limited understanding of how the pore-forming subunit, MCU, is regulated.
Recent elegant structural studies have revealed the architecture of the uniporter complex, and mechanisms
for calcium selectivity and gating, setting the stage for structure-function investigations of further channel
regulation. In this proposal, the principal investigators apply their complementary skills in structural biology
and mitochondrial functional assays to define pharmacological and protein-based mechanisms for such
channel regulation. First, using a combination of computational, electrophysiological, and structural
approaches, we will investigate uniporter inhibitors that are cell-permeable and specific, and useful for either
acute or chronic injury. Second, using new molecular tools, mutagenesis, and structural biology, we will
identify how the uniporter subunit MCUB leads to inhibition of calcium uptake through the uniporter. Taken
together, our studies will reveal novel forms of uniporter regulation that may be developed into therapies for
cardiovascular and other disorders.

Grant Number: 5R01HL165797-04
NIH Institute/Center: NIH
Principal Investigator: Dipayan Chaudhuri