# The contribution of mitochondrial DNA damage to diabetes-related beta-cell failure

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $73,828

## Abstract

PROJECT SUMMARY
This F32 proposal describes a comprehensive training and mentorship program for Dr. Rebecca Davidson,
a postdoctoral research fellow in the Department of Internal Medicine at the University of Michigan. Dr. Davidson
will participate in a rigorous training plan, guided by their mentor along with a multi-disciplinary advisory
committee. Their training program will include hands-on molecular, bioinformatics, and physiological training, as
well as mentored opportunities to engage in scientific writing, presentations, and grant applications. The ultimate
goal of this proposal is to best position Dr. Davidson for an independent and productive scientific career. Diabetes
is a global epidemic of increasing prevalence, where all forms of diabetes are linked by insufficient β-cell function
or mass to meet peripheral insulin demands. Type 2 diabetes (T2D) is a metainflammatory disease additionally
characterized by impairments in mitochondrial function and ultrastructure that contribute to overall disruption of
β-cell function. Mitochondria rely on their own 16.6 kilobase-pair circular genome to generate the machinery
required for oxidative phosphorylation. Recently, our group identified a reduction in mitochondrial DNA (mtDNA)
copy number in islets from T2D donors compared to islets from non-diabetic donors, indicating a disruption in
genome stability in diabetes. While mtDNA genome instability is implicated in several diseases, its impact on β-
cell dysfunction in diabetes has yet to be explored. The long-term objective of my project is to better
understand the molecular mechanisms underlying mitochondrial dysfunction in diabetic settings. My project
focuses on the β-cell-specific role of mitochondrial genome integrity on maintaining healthy mitochondrial
function to meet the energy demands of the β cell. My preliminary data indicate that the progressive accumulation
of deletions in β-cell mtDNA impair glucose homeostasis and β-cell function. Thus, I hypothesize that loss of
mtDNA genome integrity occurs in the presence of inflammatory stressors and contributes to mitochondrial and
β-cell failure in diabetes, which I will test through 2 Specific Aims. Aim 1 will determine the importance of mtDNA
genome integrity to β-cell function and survival in mouse models of β-cell-specific mtDNA disruptions. Aim 2 will
evaluate how diabetogenic stressors impact mtDNA genome integrity utilizing primary human islets and mouse
models of diabetes. Successful completion of these Aims will provide novel and critical insights into the
mechanistic contribution of mtDNA genome integrity on overall mitochondrial health and β-cell function required
to preclude diabetes development.

## Key facts

- **NIH application ID:** 10997111
- **Project number:** 1F32DK141236-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rebecca K Davidson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997111

## Citation

> US National Institutes of Health, RePORTER application 10997111, The contribution of mitochondrial DNA damage to diabetes-related beta-cell failure (1F32DK141236-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997111. Licensed CC0.

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