# The role of calcium entry through the mitochondrial uniporter in regulating cardiac metabolism and physiology

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $668,781

## Abstract

The entry of calcium into the mitochondria is fundamentally important in regulating bioenergetic
capacity and modulating cell death thresholds. For nearly fifty years, mitochondria were known
to have a selective calcium-selective pore in the inner mitochondrial membrane. Entry of
calcium through this pore, often termed the calcium uniporter, was believed to be essential in
boosting ATP production by augmenting the activity of multiple calcium-sensitive mitochondrial
matrix enzymes. This increase in mitochondrial calcium therefore allowed for a rapid but
regulated increase in mitochondrial ATP under conditions of increased energetic demand. While
under these conditions, the entry of calcium appears beneficial, additional evidence suggested
that excessive calcium entry triggers a mitochondrial cell death program characterized by
opening of the mitochondrial permeability transition pore (mPTP). Such situations appear to be
particularly relevant to tissue injury occurring in the setting of ischemia-reperfusion injury. While
considerable electrophysiological, biophysical and physiological data existed on the
mitochondrial inner membrane calcium pore, its molecular identity remained elusive for over fifty
years. That situation has demonstrably changed in the last five years with the rapid
identification of the components of the inner mitochondrial calcium uniporter complex (MCUC)
now known to be composed of at least four proteins. These components include the pore-
forming protein MCU, its apparent membrane scaffold EMRE and two calcium-sensitive
regulators MICU1 and MICU2. The molecular identity of the MCUC paved the way for the
creation of mouse models in which one or more component of the complex has been deleted.
This, in turn, allows for a more detailed and precise analysis of the physiological role of
mitochondrial calcium in regulating both bioenergetics and cell death. Here, we propose to
analyze the role of the MCUC in basal and stress-induced cardiovascular physiology. Our
particular emphasis will be on the role of the MCUC in ischemia/reperfusion injury, metabolism
and aging. This analysis, we believe, will increase our fundamental understanding of both
mitochondrial biology and cardiac physiology and potentially pave the way for new treatment
strategies targeting a diverse array of conditions ranging from reperfusion injury to the age-
dependent decline in cardiac function.

## Key facts

- **NIH application ID:** 9859449
- **Project number:** 5R01HL142589-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** TOREN FINKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $668,781
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859449

## Citation

> US National Institutes of Health, RePORTER application 9859449, The role of calcium entry through the mitochondrial uniporter in regulating cardiac metabolism and physiology (5R01HL142589-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859449. Licensed CC0.

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