# Role of Protein Import in the Development of the Diabetic Heart

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2024 · $533,177

## Abstract

PROJECT SUMMARY
Cardiovascular complications account for the majority of deaths in diabetic patients. Mitochondrial dysfunction
is central to the disease and it precipitates contractile impairment, leading to death. However, the precise
mechanisms that cause mitochondrial dysfunction in the diabetic heart remain unclear. Using type 2 diabetic
human (patient) and mouse (db/db) models, we observed pronounced disruption to mitochondrial structure and
function, which were associated with the loss of mitochondrial proteins. The vast majority of mitochondrial
proteins are nuclear genome-encoded and require import into the mitochondrion. Import occurs through a
coordinated set of machinery containing an active motor, driven by mitochondrial heat shock protein 70
(mtHsp70). We observed decreased mtHsp70 content in cardiac mitochondria from type 2 diabetic patients and
db/db mice, and a decrease in mitochondrial protein import. Following import, mitochondrial proteins are refolded
into native structures to become functional. MtHsp70 also participates in the refolding process, and works
synergistically with Lon Peptidase 1, Mitochondrial (LonP1), an AAA+ protease of the mitochondrial matrix. We
have also observed a decrease in LonP1 in the type 2 diabetic heart. When mitochondrial protein import is not
functioning properly, aggregated nuclear genome-encoded proteins accumulate on the exterior of the
mitochondrion leading to a phenomenon termed mitochondrial precursor over-accumulation stress. Currently, it
is unclear what factors contribute to a decrease in protein import efficiency and refolding or whether manipulation
of these processes can restore mitochondrial proteomic make-up, mitochondrial function and cardiac contractile
performance in the diabetic heart. Our proposed studies address this critical gap in knowledge. The information
will enhance our understanding of these processes and aid in the development of therapeutic strategies that
target specific import constituents that contribute to loss of mitochondrial proteins. The central hypothesis to be
tested is that decreased protein import and refolding in the type 2 diabetic heart causes loss of mitochondrial
proteins and mitochondrial precursor over-accumulation stress leading to mitochondrial dysfunction and
contractile impairment. The objectives of this application are to (1) identify submitochondrial locations where
protein import is compromised in type 2 diabetic mitochondria and the impact on import machinery; (2) evaluate
the impact of type 2 diabetes mellitus on mitochondrial protein refolding and the synergistic influence of mtHsp70
and LonP1; and (3) determine the extent of mitochondrial and proteomic stress that occurs in the type 2 diabetic
heart, due to failed mitochondrial protein import contributing to mitochondrial precursor over-accumulation stress.
Completion of these studies is expected to provide fundamental molecular insight into the mechanisms
contributing to the loss of nucl...

## Key facts

- **NIH application ID:** 10811619
- **Project number:** 5R01HL168290-02
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** John M Hollander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $533,177
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811619

## Citation

> US National Institutes of Health, RePORTER application 10811619, Role of Protein Import in the Development of the Diabetic Heart (5R01HL168290-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10811619. Licensed CC0.

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