Ample evidence suggests that a dramatic decrease in mitochondrial Ca2+ retention may contribute to cell death associated with stroke, excitotoxicity, ischemia and reperfusion, and neurodegenerative diseases. Mitochondria from all known tissues can accumulate and store Ca2+, but the maximum Ca2+ storage capacity varies widely and exhibits striking tissue specificity. There is currently no explanation to this fact. A precipitation of Ca2+ and phosphate in the mitochondrial matrix has been suggested to be the form of storage of accumulated Ca2+ in mitochondria. How this precipitate is formed is not known. On the basis of earlier observations and our current data we hypothesize that Ca2+ and phosphate precipitation in the mitochondrial matrix is catalyzed by a specific factor, which serves as a nucleation center for the formation of the precipitate. The amount of this factor determines the maximum mitochondrial Ca2+- storage capacity. Accumulation of Ca2+ above a tissue-specific storage threshold activates a proteinaceous channel termed """"""""permeability transition pore"""""""" (PTP) in the inner membrane of mitochondria. Opening of PTP results in energy deprivation, oxidative stress and may cause cell death. There is no consensus model of PTP that would encompass most of its known structural and regulatory properties and explain its activation by Ca2+ and phosphate. Past studies revealed aspects of PTP structure and regulation, but the molecular identity of its key element, the channel-forming protein(s) is not known. We propose a radically novel model of PTP activation by accumulated Ca2+ and phosphate;we also propose most plausible candidate on the role of PTP channel-forming protein.
The specific aims of this project are designed to prove the two key elements of our hypothesis by (1) proving the role of the suggested protein in PTP activation and (2) identifying the nucleation factor responsible for the formation of Ca2+ and phosphate precipitate in the mitochondrial matrix. This project will lay the foundation for the molecular etiology of Ca2+-induced mitochondrial dysfunctions and cell death. It could immensely contribute to the development of targeted interventions and drugs combating the neurodegenerative diseases, stroke, excitotoxic and ischemia- reperfusion induced tissue damage.

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NARRATIVE. This project aims to verify a radically novel model of permeability transition pore (PTP) activation by accumulated Ca2+ and phosphate and to prove the role of gC1qR protein in the formation of the PTP channel. It also aims to identifying the nucleation factor responsible for the formation of Ca2+ and phosphate precipitate in the mitochondrial matrix and interaction of this factor with gC1qR protein.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sutherland, Margaret L
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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