# Control of beta cell identity by the mitochondrial life cycle

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Diabetes results from insufficient functional pancreatic β-cell mass to meet peripheral insulin demands. β-cell
failure can occur in T2D due to loss of β-cell identity or de-differentiation, with recent studies suggesting that loss
of the mitochondrial gene expression program heralds the immature β-cell state. β-cells rely upon mitochondrial
respiration to generate the energy necessary for the metabolic demands of insulin biosynthesis, processing, and
secretion. Indeed, defects in mitochondrial structure, function, and DNA levels have been reported in the β-cells
of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of
impairments in the mitochondrial life cycle, which maintains functional mitochondrial mass via a balance of
biogenesis and turnover. It is not clear, however, if impaired mitochondria are necessary and sufficient to directly
induce β-cell immaturity. Interestingly, our preliminary data suggest that genetic loss of biogenesis or mitophagy
reduces β-cell maturity and mass, which is not due to impaired β-cell replication or survival. Therefore, our goal
is to dissect the mechanistic contribution of mitochondrial biogenesis and turnover to β-cell maturity and elucidate
their contribution to diabetes pathogenesis. The central hypothesis to be tested is that defects in the
mitochondrial life cycle induce a retrograde signaling cascade that impairs β-cell identity. We will test this
hypothesis by the following approach: Specific Aim 1 will elucidate the effect of metabolic overload on the
mitochondrial life cycle and its control of β-cell identity. Specific Aim 2 will determine the contribution of
mitochondria derived oxidative damage to the development of β-cell immaturity. Specific Aim 3 will delineate the
role of the integrated stress response to consolidate retrograde signals inducing β-cell immaturity following
mitochondrial dysfunction. We anticipate obtaining a clear understanding of the importance and translational
relevance of the mitochondrial life cycle by revealing the key effectors that mediate mito-nuclear crosstalk and
impact β-cell identity. These results should re-define the role of mitochondria in diabetes pathogenesis and could
open new possibilities to re-program immature β-cells back to a mature state to treat diabetes in Veterans.

## Key facts

- **NIH application ID:** 10106455
- **Project number:** 5I01BX004444-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Scott Soleimanpour
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106455

## Citation

> US National Institutes of Health, RePORTER application 10106455, Control of beta cell identity by the mitochondrial life cycle (5I01BX004444-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10106455. Licensed CC0.

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