# Rab GTPases-mediated mitochondrial clearance in diabetic cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $411,962

## Abstract

PROJECT SUMMARY
Diabetic cardiomyopathy is a common yet underestimated cause of heart failure and mortality in patients with
diabetes. The underlying basis of this often-fatal syndrome is unknown, although multiple pathways converge
on a common denominator - dysfunctional mitochondria. Understanding how damaged mitochondria are
removed is critical, as the presence of damaged mitochondria leads to rapid generation of reactive oxygen
species which then affect the remaining healthy mitochondria. This leads to wide-spread mitochondrial
dysfunction and cell death. Although damaged mitochondria are believed to be degraded by mitochondrial
autophagy (a specific form of autophagy), we have recently discovered the existence of a novel endosomal-
mediated mitochondrial degradation pathway in cardiomyocytes exposed to hyperglycemia. The suppression of
this pathway is potentially linked to increased susceptibility against diabetic cardiomyopathy. This observation
was possible due to our ability to generate patient-specific induced pluripotent stem cells (iPSCs) from diabetic
patients with (T2DCM) and without (T2D) cardiomyopathy. We found that only T2D cells, but not T2DCM,
exhibited increased endosomal-mediated mitochondrial degradation. However, neither the molecular cues
regulating this novel pathway, nor the functional significance of this endosomal pathway, is established in
cardiomyocytes from a diabetic heart. Thus, the goal of this project is to demonstrate the functional significance
of the endosomal-mediated mitochondrial degradation pathway during diabetic cardiomyopathy and to elucidate
the underlying mechanisms regulating this pathway. Aim 1 will define the functional role of endosomal-mediated
mitochondrial clearance in the diabetic heart by disrupting the function of Rab5 and Rab7, key determinants of
the endo-lysosomal system. These studies will employ multiple innovative reagents, including CRISPR-mediated
Rab knockout and overactivation iPSC lines and a novel inducible, cardiac-specific Rab7 knockout mouse model,
to interrogate the importance of these Rabs in maintaining functional mitochondrial degradation in two distinct
diabetic mouse models. Aim 2 will define the role of VPS34/UVRAG in generating phosphatidylinositol 3-
phosphate (PI3P) required for endosomal maturation and hence clearance of defective mitochondria. We have
supporting data that mTOR is excessively upregulated in selected diabetic patients leading to phosphorylation
of UVRAG, impairing its function to form a complex with VPS34 in generating PI3P for proper endosomal
maturation and mitochondria degradation. Using both genetic and pharmacological methods, we will
demonstrate that maintaining a stable UVRAG/VPS34 complex is a prerequisite for PI3P to mediate conversion
of Rab5 into Rab7 for endosomal-mediated mitochondrial degradation. Collectively, these innovative studies will
illuminate a novel endosomal-mediated mitochondrial degradation pathway as an important adaptive...

## Key facts

- **NIH application ID:** 10126896
- **Project number:** 5R01HL148756-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Sang Ging Ong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,962
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126896

## Citation

> US National Institutes of Health, RePORTER application 10126896, Rab GTPases-mediated mitochondrial clearance in diabetic cardiomyopathy (5R01HL148756-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126896. Licensed CC0.

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