# Non-canonical roles for ATM kinase in regulating mitochondrial function and redox homeostasis

> **NIH NIH F31** · DUKE UNIVERSITY · 2024 · $41,391

## Abstract

PROJECT SUMMARY.
Ataxia-telangiectasia (A-T) is a pleiotropic genetic disorder caused by bi-allelic mutations in the Ataxia-
telangiectasia, mutated (ATM) gene. A-T leads to numerous clinical symptoms, including radiosensitivity, sterility,
immunodeficiency, insulin resistance, neurodegeneration, and progressive pulmonary dysfunction. Many of
these symptoms are attributed to dysfunction in DNA damage signaling, ATM’s canonical function. However,
several of the hallmark symptoms of A-T align with the clinical presentation of mitochondrial dysfunction.
Mitochondria regulate a variety of cellular functions, including cellular respiration and calcium signaling. Due to
their role in oxidative phosphorylation, mitochondria are exposed to reactive oxygen species (ROS)-mediated
damage. The specific autophagic degradation of mitochondria, mitophagy, is essential for the degradation of
damaged mitochondria. Impaired mitophagy causes increased cellular ROS, leading to cellular dysfunction that
eventually results in aging, cancer development, and neurodegeneration. The Kastan lab has previously
characterized mitochondrial dysfunction in primary ATM-/- murine cells, indicating that ATM regulates
mitochondrial, metabolic, and redox homeostasis. Additionally, the Kastan lab has reported that mono-allelic
deletion of the autophagy regulating protein Beclin-1 rescues many aspects of mitochondrial dysfunction in ATM-
/- cells, although the relationship between ATM and Beclin-1 remains undefined. Preliminary data outlined in this
proposal indicates that CRISPR/Cas9 deletion or pharmacological inhibition of ATM causes mitochondrial
dysfunction in immortalized cells, including increased mitochondrial mass and ROS. I have also demonstrated
that mitochondrial stress leads to activation of ATM and its downstream effector kinase Chk2. In order to further
elucidate the molecular pathways by which ATM regulates mitochondrial function, we have performed unbiased
proteomic screens to identify interactors of both ATM and Beclin-1. These screens identified GRP94 and
LRPPRC as putative ATM and Beclin-1 interactors. Specifically, the endoplasmic reticulum protein GRP94 is
reported to regulate autophagy, calcium flux, and cellular response to ROS; overexpression of GRP94 is
implicated in tumor development and neurodegenerative disease. LRPPRC is a mitochondrial protein involved
in the regulation of mitochondrial ROS and electron transport chain (ETC) activity. Mutations in LRPPRC lead to
ataxia and neurodegeneration, similar to A-T. The experiments proposed herein will validate the interactions
between ATM and its putative interactors, GRP94 and LRPPRC, and determine whether these proteins are direct
substrates of ATM. Then, I will determine the functional impact of these relationships on mitochondrial/metabolic
function and redox homeostasis, including mitochondrial mass, mitochondrial ROS, ETC activity, and oxygen
consumption rate will be further characterized. Additionally, th...

## Key facts

- **NIH application ID:** 10818529
- **Project number:** 5F31CA268774-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Paige Elizabeth Burrell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,391
- **Award type:** 5
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818529

## Citation

> US National Institutes of Health, RePORTER application 10818529, Non-canonical roles for ATM kinase in regulating mitochondrial function and redox homeostasis (5F31CA268774-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10818529. Licensed CC0.

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