# Molecular examination of mitochondrial calcium control

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $698,609

## Abstract

Abstract
 Ca2+ elevations in the heart can serve as a signal for augmented energy output from
the mitochondria by directly increasing the activity of the electron transport chain and
select dehydrogenases. However, at the same time sustained elevations in Ca2+ that
occurs acutely after myocardial infarction injury can cause cardiomyocyte necrotic and
apoptotic death through opening of the mitochondrial permeability transition pore (PTP).
The mitochondrial Ca2+ uniporter (MCU) complex imports Ca2+ across the inner
membrane into the mitochondrial matrix where it can affect both energy production and
PTP opening during acute ischemic injury. Hence the MCU complex and many of the
more recently described genes that constitute it could be novel therapeutic targets for
drug design with the goal of reducing cardiomyocyte death or altering cardiac metabolic
performance. The genes that comprise the MCU were only recently identified hence the
field is still in its infancy with respect to genetically correlating mitochondrial Ca2+
regulation with cardiac physiology and pathophysiology in vivo. Here we propose to use
mice lacking some of these key molecular regulators of mitochondrial Ca2+ handling to
decode and differentiate between physiological and pathological Ca2+ signals at baseline
and with disease. Our overarching goal is to examine how mitochondrial Ca2+ influx and
efflux regulates cardiac life, death and metabolism. However, no single cardiac
laboratory in our field has the underlying expertise to both characterize the complex
biophysics of mitochondrial Ca2+ handling and at the same time employ the necessary
mouse genetics and cell biology to truly achieve the stated goals of this project. Hence,
we are requesting to renew our collaborative dual-PI proposal that will be 50/50 effort
between the Molkentin and Bers laboratory, to wed the very best in mouse molecular
genetics and cardiac physiology with innovative assessment of mitochondrial and
intracellular Ca2+ imagining and PTP activity, respectively. Our Aims will be: Aim 1:
Examine how MCUb and the MCU complex regulates myocyte [Ca]Mito to affect
metabolism and PTP opening with IR injury, Aim 2: Elucidate NCLX regulation in cardiac
function, PTP opening and cell death after IR injury, and Aim 3: Identify the alternate /
slow [Ca]Mito influx effectors that operate independent of MCU in the heart. The 2 PIs
have a strong track record of working together with multiple shared publications and joint
grants. Hence, they represent an ideal melding of 2 divergent laboratory skill sets that
are needed to truly understand mitochondrial Ca2+ regulation and its effect on cardiac
physiology and disease responsiveness.

## Key facts

- **NIH application ID:** 10320799
- **Project number:** 5R01HL132831-06
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Donald M Bers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $698,609
- **Award type:** 5
- **Project period:** 2016-07-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320799

## Citation

> US National Institutes of Health, RePORTER application 10320799, Molecular examination of mitochondrial calcium control (5R01HL132831-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320799. Licensed CC0.

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