# Ca signaling cross-talk from SR to mitochondria in heart muscle

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $649,845

## Abstract

Project Summary
Mitochondria and sarcoplasmic reticulum (SR) form close interfaces in cardiomyocytes where the
propagation of Ca signals from SR to mitochondria contributes to heart function under physiologic and
pathologic conditions. TRIC is a novel class of trimeric intracellular cation channels located at the SR
or endoplasmic reticulum (ER) of multiple cell types, which function as counter-ion channels that allow
flow of K ions into the SR/ER during the acute phase of Ca release. Genetic ablations or mutations of
TRIC channels are associated with hypertension, heart disease, respiratory defects and brittle bone
disease. The recent crystal structure of TRIC proteins confirms the homotrimeric architecture of a
cation channel. Within the human and mouse genomes, there are two TRIC isoforms, TRIC-A and
TRIC-B, that display differential functions in regulation of Ca signaling in excitable and non-excitable
cells. While our past research efforts primarily focused on understanding the physiological function for
TRIC-A in skeletal and smooth muscle and to a lesser extent the role of TRIC-B in epithelial cells, the
role of TRIC in cardiac physiology and disease remains largely unexplored. Here we present evidence
that TRIC-A, in addition to modulation of the SR permeability to K ions, functions as an integral
component of the physiological control mechanism of Ca signaling in cardiac muscle. We found that the
carboxyl-tail domain of TRIC-A interacts with the RyR2 channel to directly modulate Ca release from the
SR. The TRIC-A-/- mice develop arrhythmia, severe cardiac hypertrophy and fibrosis following
isoproterenol treatment or transverse aortic constriction (TAC) surgery. Isolated TRIC-A-/-
cardiomtocytes display mitochondria dysfunction that likely reflects SR Ca overload-induced
mitochondria toxicity under stress conditions. As uncontrolled Ca release has been implicated in
mitochondrial dysfunction in cardiac pathology, we hypothesize that “TRIC interaction with RyR2
modulates SR Ca release and crosstalk with mitochondria. Absence of TRIC leads to Ca overload
inside SR and causes stress-induced Ca toxicity to mitochondria. The dysregulated SR-mitochondria
crosstalk contributes to the development of heart failure”. We further propose that targeting TRIC-
mediated SR-mitochondria crosstalk represents a novel means for treatment of cardiovascular
diseases. Our experiments designed in this project contain two specific aims: Aim 1 - to define the
functional interaction between TRIC-A/B and RyR2 in regulating the cross-talk of Ca signaling from SR
to mitochondria in cardiomyocytes under physiologic and pathologic conditions; and Aim 2 - to elucidate
the in vivo role of TRIC-A in mediating stress-induced changes in heart function.

## Key facts

- **NIH application ID:** 9908165
- **Project number:** 5R01HL138570-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Pei-Hui Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $649,845
- **Award type:** 5
- **Project period:** 2018-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908165

## Citation

> US National Institutes of Health, RePORTER application 9908165, Ca signaling cross-talk from SR to mitochondria in heart muscle (5R01HL138570-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9908165. Licensed CC0.

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