# Mitochondria and arrhythmogenic calicum cycling dynamics in the heart

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $688,600

## Abstract

Project Summary
The interactions between mitochondrial metabolism and excitation-contraction coupling play important roles in
regulating normal cardiac functions and arrhythmogenesis. In ventricular myocytes, calcium (Ca) is released
from the sarcoplasmic reticulum (SR) via the ryanodine receptors (RyRs) and reuptaken back to the SR via the
sarco/endoplasmic Ca ATPase (SERCA) pump. During this cycle, mitochondria also uptake Ca and then release
it, serving as cytosolic Ca buffers. A ventricular myocyte contains ~7,000 mitochondria and >20,000 Ca release
units (CRUs) which are intermingled in space, forming a complex coupling network with local interactions that
can cause spatiotemporal subcellular dynamics (e.g. waves and oscillations) of Ca cycling and metabolism.
Under the normal condition, a low level of free Ca is needed in the mitochondria to regulate ATP production
accompanied with a small amount of reactive oxygen species (ROS) generation by the electron transport chain.
Under metabolic stress, mitochondria depolarize, which affect Ca cycling and action potential (AP) dynamics,
and induce arrhythmias via different pathways and feedback loops, including: 1) release of a large amount of Ca
from the mitochondria to directly affect Ca cycling dynamics and signaling; 2) generation of a large amount of
ROS increases ryanodine receptor (RyR) open probability and alters SERCA activity via activation of CaMKII
and PKA signaling or redox regulation; 3) lowering ATP production; and 4) reducing gap junction coupling and
increasing dispersion of excitability in tissue. In addition, Ca sparks occur randomly due to random L-type Ca
channel and RyR openings. Similarly, mitochondrial membrane potential flickering and ROS flashes also occur
randomly at the single mitochondrion level. Therefore, to understand the mechanisms of arrhythmias caused by
metabolic stress and to identify potential effective therapeutic targets, systems approaches that consider the
complex and multiscale regulations are required. This project proposes to combine experiments and multiscale
modeling as well as nonlinear dynamics to investigate the spatiotemporal subcellular Ca cycling dynamics and
arrhythmogenesis caused by metabolic stress with the following specific Aims: Aim #1. To develop spatially-
detailed mouse and rabbit ventricular myocyte models composed of networks of coupled mitochondria and CRUs
and use them to investigate the effects of metabolic stress on spatiotemporal subcellular Ca cycling dynamics
and cellular AP dynamics; Aim #2. To investigate the effects of metabolic stress on spatiotemporal subcellular
Ca cycling dynamics and cellular AP dynamics in ventricular myocytes isolated from different animal models,
including wild type, Cyclophilin D knockout, and mitochondrial Ca uniporter knockout mouse hearts and normal
rabbit hearts; and Aim #3. To investigate the effects of metabolic stress on ventricular arrhythmias in computer
simulation of tissue models and whol...

## Key facts

- **NIH application ID:** 9847980
- **Project number:** 5R01HL133294-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ZHILIN QU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $688,600
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847980

## Citation

> US National Institutes of Health, RePORTER application 9847980, Mitochondria and arrhythmogenic calicum cycling dynamics in the heart (5R01HL133294-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847980. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*