# FUNDC1 and diabetic cardiomyopathy

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $705,028

## Abstract

Project Summary
Mitochondria are essential for energy production, but, if damaged, they become a major source of
reactive oxygen species and proapoptotic factors. Increasing evidence suggests that mitochondrial
dysfunction is a central event in the development of diabetic cardiomyopathy. However, the molecular
mechanisms responsible for diabetes-caused mitochondrial dysfunction in cadiomyocytes remain
poorly characterized. Our exciting preliminary data included in this application show that the levels of
the FUN14 domain containing 1 (FUNDC1) protein, a mitochondrial outer-membrane protein, are
highly increased in diabetic hearts resulting in mitochondrial dysfunction and diabetic cardiomyopathy.
Mechanistically, aberrant FUNDC1 expression in diabetes increases endoplamsmic reticulum (ER)-
mitochondria contact, which promotes Ca2+ transfer from the ER to the mitochondria and thus results
in mitochondrial Ca2+ overload, cardiomyocyte death, and cardiac dysfunction. Cardiac-specific
deletion of FUNDC1 reduces ER-mitochondria contacts, attenuating cardiac dysfunction in Type I and
Type II diabetic mice. Thus, the central hypothesis of this proposal is that aberrant FUNDC1
expression in diabetes leads to cardiomyopathy by impairing mitochondrial function through
enhancement of ER-mitochondria contacts. This hypothesis will be tested by using gain-/loss-of
function and pharmacologic/genetic strategies in both animal models and cultured cardiomyocytes.
Aim 1 is to establish the essential roles of increased FUNDC1 expression in the development of
diabetic cardiomyopathy. In this Aim, we will test the hypotheis that enhanced FUNDC1 expression
causes cardiac structural damage and dysfunction by compromising mitochondrial function in
diabetes. Aim 2 is to elucidate the mechanism by which FUNDC1 upregulation in diabetes impairs
mitochondrial function, leading to cardiomyopathy. In this aim, we will test the hypothesis that
diabetes-enhanced FUNDC1 expression impairs mitochondrial function by promoting the ER-
mitochondria contacts. We will determine if FUNDC1 mediates ER-mitochondria contacts in diabetic
hearts, investigate whether increased FUNDC1 causes mitochondrial dysfunction and cardiomyocyte
death by increasing Ca2+ transfer from ER to mitochondria, and examine whether diminishing ER-
mitochondrial Ca2+ flux improves mitochondrial and cardiac function in diabetic hearts using IP3R2
cardiomyocyte-specific knockout mice. The completion of this highly innovative proposal will help
develop a new paradigm for treating diabetic cardiomyopathy.

## Key facts

- **NIH application ID:** 9859443
- **Project number:** 5R01HL137371-04
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Zhonglin Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $705,028
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-12-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859443

## Citation

> US National Institutes of Health, RePORTER application 9859443, FUNDC1 and diabetic cardiomyopathy (5R01HL137371-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859443. Licensed CC0.

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