# Mitochondrial stress shapes host responses to bacterial infection

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $414,848

## Abstract

Mitochondrial stress shapes host responses to bacterial infection
Project Summary
The mitochondrial network is a central hub for metabolism and sensing cellular stress, critical to shaping
the immune response to infection. Cardiolipin (CL), an anionic phospholipid found in bacteria and in
the inner mitochondrial membrane (IMM), anchors multi-protein respiratory chain complexes to the
membrane and may also be deployed to nucleate immune supramolecular organizing centers such as
the inflammasome. In conditions of stress, such as infection, cardiolipin is thought to translocate to the
outer mitochondrial membrane (OMM) or the extracellular space. The regulatory steps that control CL
translocation, remodeling and CL-dependent immune responses during bacterial infection are poorly
understood. Mutations in the human CL remodeling enzyme, Tafazzin, result in an X-linked multi-
system disorder known as Barth Syndrome, commonly associated with recurrent bacterial infections.
The long-term goal of this proposal is to elucidate the mechanisms by which CL localization,
modification and signaling enable mitochondrial control of the innate immune response to bacterial
pathogens. Here we propose to test the hypothesis that CL translocation and modification regulates
the switch between homeostatic and stress-responsive functions to drive innate immune responses to
methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo. Specifically, we will perturb
macrophage CL at four different steps: global biosynthesis, OMM-localization, oxidation and
remodeling and define the signaling and effector mechanisms that are CL-dependent in the context of
MRSA infection. Under these four experimental conditions, we will quantitatively track CL membrane
localization and intracellular trafficking in macrophages using super resolution microscopy coupled with
biochemical approaches. Finally, we will study the innate immune response to MRSA skin and soft
tissue infection in mice genetically deficient in OMM-localized CL or enzymatically remodeled CL. We
will also test the contribution of oxidized CL to in vivo antibacterial responses by treating MRSA-infected
mice with a CL-targeted antioxidant. These studies will yield mechanistic insight into CL localization
and remodeling during innate immune responses and potentially identify therapeutic targets for
productively modulating inflammation. Additionally, this work will help contextualize CL-dependent
innate immune signaling within the framework of a clinically relevant pathogen in vivo.

## Key facts

- **NIH application ID:** 10317161
- **Project number:** 1R01AI157384-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Mary O'Riordan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,848
- **Award type:** 1
- **Project period:** 2021-05-27 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317161

## Citation

> US National Institutes of Health, RePORTER application 10317161, Mitochondrial stress shapes host responses to bacterial infection (1R01AI157384-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10317161. Licensed CC0.

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