# Mitochondrial DNA Stress Activation of Interferon Signaling and Lupus Pathology

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $390,184

## Abstract

PROJECT SUMMARY
This is a new proposal aimed at characterizing a novel mitochondrial pathway of interferon (IFN) signaling we
discovered and to probe its relevance to autoimmune disease pathogenesis. IFNs are essential cytokines for
host defense because they provoke intrinsic antiviral states in non-immune cells and stimulate immune cells
and inflammation to combat infection. They are used therapeutically for certain autoimmune diseases, cancers,
and viral infection, but are also implicated in pathology when produced chronically or out of context. In our
studies of a Tfam+/- mouse model of mitochondrial DNA (mtDNA) stress and normal mitochondrial responses to
viral infection, we found that mtDNA release into the cytoplasm primes IFN signaling to provide enhanced
antiviral immunity. This response requires binding of mtDNA to the cytoplasmic nucleic acid sensor cGAS,
activation of the endoplasmic reticulum (ER)-resident protein STING, and downstream signaling to up-regulate
interferon-stimulated genes (ISGs) and Type 1 IFN production. ISG expression and increased Type 1 IFN
signaling contribute to the autoimmune disease systemic lupus erythematosus (SLE or lupus). Our
experimental plan will systematically interrogate key remaining questions regarding this new innate immune
signaling pathway, including how mtDNA is released and recognized by cGAS, are altered mitochondrial
dynamics and autophagy involved, and is the pathway relevant to human diseases states where mtDNA stress
has been implicated. The specific aims of the project are to 1) determine the specificity and mechanism of
mtDNA sensing by cGAS, 2) decipher the role of mitochondrial dynamics (fission, fusion, autophagy) in mtDNA
release and IFN signaling, including development of an innovative new mtDNA-release assay, and 3) test if
mtDNA stress-mediated IFN signaling contributes to lupus pathology in mouse models and human patient cells.
Significance: Completion of this project will provide significant new insight into how mtDNA stress, which is
observed in many disease conditions and aging, results in innate immune pathway activation and can lead to
autoimmune pathology via increased IFN production, even in the absence of a viral infection. By defining the
molecular mechanisms involved, new inroads into how to augment this response to enhance antiviral immunity
or prevent it under pathological circumstances (e.g. in lupus) will be made that have therapeutic potential.
Furthermore, we will gain considerable new basic biology insight into mitochondrial dynamics, cytoplasmic
nucleic acid recognition pathways, autophagy, and mechanisms of mtDNA damage, repair and modification.

## Key facts

- **NIH application ID:** 9944459
- **Project number:** 5R01AR069876-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** GERALD SHADEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,184
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944459

## Citation

> US National Institutes of Health, RePORTER application 9944459, Mitochondrial DNA Stress Activation of Interferon Signaling and Lupus Pathology (5R01AR069876-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944459. Licensed CC0.

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