# Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

PROJECT SUMMARY
Diseases that arise from mutations in components of mitochondrial oxidative phosphorylation can be
devastating, as mitochondria are crucial for energy synthesis. These diseases occur predominantly in
infants and children, with a prevalence of 1 in 5000. Though virtually any organ can be affected, the heart is
frequently involved, because cardiac function has such high energy requirements. These mitochondrial
cardiomyopathies have a particularly grim prognosis, with mortality rates increased nearly three-fold
compared to children without cardiac involvement. In linking cardiac function to mitochondrial metabolism,
calcium signaling may be central to the pathological process. Calcium influx into the mitochondria can
potently stimulate ATP synthesis, but excessive levels trigger mitochondrial failure and cell death. We
hypothesize that, when oxidative phosphorylation becomes impaired, feedback regulation causes a
compensatory increase in calcium influx, boosting ATP synthesis. However, after prolonged entry,
mitochondrial calcium levels become excessive and trigger mitochondrial failure, exacerbating cardiac
dysfunction. The rationale for this study is to determine whether such regulation exists in a well-
characterized animal model of mitochondrial cardiomyopathies, which features genetic deletion of a
mitochondrial transcription factor (Tfam) selectively in cardiomyocytes. The first aim is to determine
whether the increased mitochondrial calcium levels found in preliminary studies are truly compensatory. For
this aim, we will create animals with mitochondrial cardiomyopathies that have mitochondria that either
cannot take up calcium, or are resistant to excessive calcium levels. The second objective is to determine
the molecular mechanism causing enhanced mitochondrial calcium influx, and determine whether such
enhancement can be replicated in cardiomyocytes derived from human induced pluripotent stem cells. In
these analyses, we use an innovative set of techniques, including direct electrical measurement of
mitochondrial calcium currents, that overcome technical challenges present in studying calcium transport. If
successful, our research will define a significant new target for potential therapy in these devastating
disorders.

## Key facts

- **NIH application ID:** 10136692
- **Project number:** 5R01HL141353-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Dipayan Chaudhuri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136692

## Citation

> US National Institutes of Health, RePORTER application 10136692, Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies (5R01HL141353-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10136692. Licensed CC0.

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