# Structural-functional zoning of the mitochondrion in cardiac Ca2+, ROS, and energetics regulation

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $611,797

## Abstract

Mitochondrial impairment is a main contributor and potential therapeutic target in the
development of heart failure (HF). During excitation-contraction coupling, Ca2+ is released from
the sarcoplasmic reticulum of dyadic junction (jSR) to initiate muscle contraction. jSR is often
tethered to mitochondria, where a high [Ca2+] nanodomain is created to facilitate Ca2+
propagation to the mitochondrial matrix to stimulate ATP production (excitation-energetics
coupling). The beating heart consumes much energy; thus, cardiomyocytes must be efficient in
dynamically balancing energy demands and supplies while avoiding potential Ca2+ mediated
toxicity. We find that mitochondrial Ca2+ uniporter (mtCU), responsible for Ca2+ uptake,
concentrate to hotspots at the interface with jSR whereas the robust Na+-dependent Ca2+
extrusion (mitochondrial Na+/Ca2+ exchanger, NCLX) is mostly excluded from these segments.
In this proposal, we put forward the overarching theme that the mitochondria, which associate
with jSR, remodel their membrane structure and protein distribution asymmetrically into two
zones proximal and distal from jSR, to protect their long-term integrity while serving the
excitation-energetics coupling. Imbalance in this adaptation leads to HF. Based on our
preliminary data and published literature; we hypothesize that mitochondrial Ca2+ influx and
efflux are uniquely distanced, and so a [Ca2+] gradient is created in the matrix to ensure an
effective Ca2+ mediated energy production without toxicity by minimizing the amount of Ca2+
required to cycle through the matrix for a given [Ca2+] rise. The mitochondrial zone proximal to
the jSR forms a Ca2+ receptacle with enhanced Ca2+ entry but limited exit and less membrane
barriers for diffusion, while the mitochondrial zone distal to jSR has dense cristae membrane for
vigorous ATP generation without subjecting to Ca2+ toxicity. Finally, the constant high Ca2+ in
Ca2+ receptacle zone renders it more susceptible for physiological mitophagy via mitochondrial
fission. However, prolonged stress turns this physiological defense mechanism maladaptive,
with excess of fragmented mitochondria without jSR Ca2+ input (no excitation-energetics
coupling) due to the loss of juxtaposition, as such leads to HF etiology. Three specific aims are:
1) Investigate the physiological implications of differential submitochondrial distribution of
mitochondrial Ca2+ uptake and extrusion mechanisms in excitation-energetics coupling. 2. To
establish submitochondrial structural zoning associated with the zonal Ca2+ transport. 3. To
assess the impact of zoning on mitochondrial maintenance/quality control and how excessive
fragmentations associated with stresses could turn zoning maladaptive and lead to HF.

## Key facts

- **NIH application ID:** 10133720
- **Project number:** 5R01HL142864-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** GYORGY CSORDAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $611,797
- **Award type:** 5
- **Project period:** 2018-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133720

## Citation

> US National Institutes of Health, RePORTER application 10133720, Structural-functional zoning of the mitochondrion in cardiac Ca2+, ROS, and energetics regulation (5R01HL142864-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133720. Licensed CC0.

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