# Role of ER-mitochondria contact sites in Right Ventricular Fibrosis

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $587,749

## Abstract

Endoplasmic reticulum (ER)-mitochondrial (ER-Mito) microdomains play significant roles in the maintenance of
bioenergetics and basal cell functions via the exchange of lipids, Ca2+, and reactive oxygen species (ROS). Genetic
inhibition of mitofusin 2 (Mfn2), one of the key components of ER-Mito tethering, in cardiomyocytes (CMs) revealed
the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a differentiated form
of ER in muscle cells, for maintaining normal mitochondrial Ca2+ (mtCa2+) handling and bioenergetics in the heart.
However, it is still unclear which cellular signaling mechanism modulates Ca2+ handling at the ER/SR-Mito
microdomains in the heart during cardiac stress, and how this alters mtCa2+ and mitochondrial ROS (mROS) levels
in cardiac pathology. Our preliminary studies show that 1) Mfn2 is likely a c-Src substrate in mitochondria; 2) c-Src
can phosphorylate the C-terminal tail of Mfn2 at the outer mitochondrial membrane (OMM), a domain critical for
Mfn2 dimerization and redox sensing; and 3) c-Src-dependent tyrosine phosphorylation (P-Tyr) of Mfn2 decreases
the ER-Mito distance and facilitates ER-to-Mito Ca2+ transfer, followed by increases in mROS. Importantly, using a
preclinical rat model of pulmonary arterial hypertension (PAH) with right ventricular (RV) hypertrophy, fibrosis, and
failure, we found significant c-Src activation occurs only in cardiac fibroblasts (CFs) but not in CMs in the RV under
PAH, which subsequently causes a c-Src-dependent P-Tyr of Mfn2, decreased ER-Mito distance, increased mtCa2+
uptake and mROS, CF activation, and RV fibrosis. Similar preliminary results were obtained in RV tissue samples
from a pulmonary hypertension patient. Lastly, we found that mtCa2+ uptake via mtCa2+ uniporter (MCU) is required
for mROS elevation and subsequent activation of proliferative signaling in CFs. Based on these preliminary data, we
hypothesize that 1) c-Src-dependent P-Tyr of Mfn2 alters the ER-Mito tethering structure and causes increases in
mtCa2+ and mROS that promote CF activation, thereby acting as a molecular “switch” for the activation of RV-CFs in
PAH; and 2) CF-specific inhibition of c-Src at the OMM in vivo can be leveraged as a novel therapeutic strategy to
attenuate cardiac fibrosis in response to stress/injury such as PAH. The long-term goals of our study are to precisely
understand 1) the molecular basis of ER-Mito microdomain-mediated regulation of CF functions under pathological
conditions including PAH; and 2) develop novel therapeutic approaches targeting cardiac fibrosis-specific molecular
mechanisms.
In Aim 1, we
will establish Mfn2 as a novel c-Src substrate in mitochondria and assess the impact of
c-Src-dependent P-Tyr of Mfn2 on ER-mitochondria tethering, Ca2+ transport to mitochondria, mROS generation,
and downstream CF signaling activation using cellular systems. In Aim 2, we will specifically inhibit mitochondrial c-
Src only in the quiescent CFs by CF-specif...

## Key facts

- **NIH application ID:** 10980283
- **Project number:** 1R01HL171710-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bong Sook Jhun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $587,749
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980283

## Citation

> US National Institutes of Health, RePORTER application 10980283, Role of ER-mitochondria contact sites in Right Ventricular Fibrosis (1R01HL171710-01A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10980283. Licensed CC0.

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