We previously identified a novel mechanism that directly links the inositol trisphosphate receptor (InsPSR) Ca2+ release ion channel to programmed cell death. We extended our new insights into the biochemical and functional interactions of the InsPSR and anti-apoptotic Bcl-2 family proteins with the discovery of an essential requirement of InsPSR activity to suppress macroautophagy and maintain efficient mitochondrial respiration and normal cell bioenergetics. The InsPSR participates in generation of complex Ca2+ signals that regulate many physiological processes in cells, including, as we have discovered, autophagy and basal metabolism, as well as cell survival and death decisions. The studies undertaken to explore this regulation have led to the development of an important new paradigm regarding the regulation of cellular bioenergetics that involves a ubiquitous pathway involving constitutive Ca2+ delivery from the ER to mitochondria mediated by Ca2+ release through the InsPSR and Ca2+ uptake by the mitochondrial Ca2+ uniporter complex. Although our studies have previously defined many of the features of the InsPSR ion channel, the details of the mechanisms of permeation, gating and regulation of the complex of the mitochondrial Ca2+ uniporter are largely unknown. Our preliminary studies suggest that whereas normal and cancer cells have a similar reliance on constitutive mitochondrial Ca2+ uptake for maintenance of optimal bioenergetics, cancers cells are addicted to it since they cannot survive when it is blocked. The mechanisms that underlie this differential sensitivity between normal and cancer cells remain to be elucidated, with obvious clinical relevance. We will employ biophysical (electrophysiology, optical imaging), biochemical, genetic and cell biological approaches to define the mechanistic and structural basis for the uniporter Ca2+ channel complex. Furthermore, we will define the roles of this complex and the InsPSR as molecular targets for cancer cell growth, by use of metabolomics, cell biological and genetic approaches and in vitro and in vivo mouse models.

Public Health Relevance

The ubiquitous expression of constitutive ER-mito Ca2+ transfer has relevance for many physiological and pathophysiological processes, including cancer. A complete molecular understanding of the Ca2+ uniporter complex and appreciation of how cancer cells are addicted to its activity will provide insights that may lead to therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM056328-18
Application #
8962230
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nie, Zhongzhen
Project Start
1999-02-01
Project End
2021-03-31
Budget Start
2016-05-15
Budget End
2017-03-31
Support Year
18
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mak, Don-On Daniel; Foskett, J Kevin (2017) Ryanodine receptor resolution revolution: Implications for InsP3 receptors? Cell Calcium 61:53-56
Payne, Riley; Hoff, Henry; Roskowski, Anne et al. (2017) MICU2 Restricts Spatial Crosstalk between InsP3R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU. Cell Rep 21:3141-3154
Arduino, Daniela M; Wettmarshausen, Jennifer; Vais, Horia et al. (2017) Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening. Mol Cell 67:711-723.e7
Lovy, Alenka; Foskett, J Kevin; Cárdenas, César (2016) InsP3R, the calcium whisperer: Maintaining mitochondrial function in cancer. Mol Cell Oncol 3:e1185563
Vais, Horia; Mallilankaraman, Karthik; Mak, Don-On Daniel et al. (2016) EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter. Cell Rep 14:403-410
Yang, Jun; Vais, Horia; Gu, Wenen et al. (2016) Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability. Proc Natl Acad Sci U S A 113:E1953-62
Cárdenas, César; Müller, Marioly; McNeal, Andrew et al. (2016) Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria. Cell Rep 14:2313-24
Vais, Horia; Tanis, Jessica E; Müller, Marioly et al. (2015) MCUR1, CCDC90A, Is a Regulator of the Mitochondrial Calcium Uniporter. Cell Metab 22:533-5
Foskett, J Kevin; Philipson, Benjamin (2015) The mitochondrial Ca(2+) uniporter complex. J Mol Cell Cardiol 78:3-8
Mallilankaraman, Karthik; Cárdenas, César; Doonan, Patrick J et al. (2015) MCUR1 is an essential component of mitochondrial Ca(2+) uptake that regulates cellular metabolism. Nat Cell Biol 17:953

Showing the most recent 10 out of 24 publications