Mitochondria-derived vesicles deliver antimicrobial reactive oxygen species to control phagosome-localized staphylococcus aureus
Open accessAbstract
Pathogenic bacteria taken up into the macrophage phagosome are the target of many anti-microbial mechanisms. Although mitochondria-derived antimicrobial effectors like reactive oxygen species (mROS) aid in bacterial killing, it is unclear how these effectors reach bacteria within the phagosomal lumen. We show here that endoplasmic reticulum stress triggered upon methicillin-resistant Staphylococcus aureus (MRSA) infection induces mROS that are delivered to bacteria-containing phagosomes via mitochondria-derived vesicles (MDVs). The endoplasmic reticulum stress sensor IRE1α induces mROS, specifically hydrogen peroxide (mH 2 O 2), upon MRSA infection. MRSA infection also stimulates the generation of MDVs, which require the mitochondrial stress response factor Parkin, and contributes to mH 2 O 2 accumulation in bacteria-containing phagosomes. Accumulation of phagosomal H 2 O 2 requires Toll-like receptor signaling and the mitochondrial enzyme superoxide dismutase-2 (Sod2), which is delivered to phagosomes by MDVs. Sod2 depletion compromises mH 2 O 2 production and bacterial killing. Thus, mitochondrial redox capacity enhances macrophage antimicrobial function by delivering mitochondria-derived effector molecules into bacteria-containing phagosomes.
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S.a.-infected RAW cells showed increased matrix mtROS production; treatment with Necrox-5 reduced matrix mtROS levels and increased bacterial burden.
“S.a.-infected RAW cells showed increased matrix mtROS production and treatment with Necrox-5, a rarely used mitochondrial matrix ROS scavenger, did not only reduce matrix mtROS levels but also increased bacterial burden indicating a role for matrix mtROS for defense against S.a.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [252]
Abuaita et al. suggested that TLR signaling induces delivery of mitochondria-derived vesicles containing SOD2 to S.a.-containing phagosomes, where SOD2 enhances conversion of O2− to H2O2.
“Abuaita et al. suggested that TLR signaling, instead of triggering mtROS production, induces the delivery of mitochondria-derived vesicles containing the mitochondrial matrix protein SOD2 to S.a.-containing phagosomes. In the phagosomal lumen, the delivered SOD2 then enhances conversion of O2●− to H2O2.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [252]
A clear role for either Nox2-derived ROS or mtROS in direct antibacterial defense of macrophages against S.a. remains not fully characterized.
“A clear role for either Nox2-derived ROS or mtROS in direct antibacterial defense of macrophages against S.a. therefore remains not fully characterized.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [252]
TLR2/4/9-deficient RAW cells infected with S.a. showed unaltered matrix mtROS production, while bacterial burden was reduced.
“TLR-mediated signaling can induce mtROS production [30,61], but in contrast TLR2/4/9-deficient RAW cells infected with S.a. showed unaltered matrix mtROS production, while bacterial burden, however, was reduced.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [252]
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References 51 · Cited by 223
- Authors
- Abuaita, B. H., Schultz, T. L., & O’Riordan, M. X.
- Affiliations
- University of Michigan (US)
- Corresponding author
- O’Riordan, Mary X.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 24
- Issue
- 5
- Pages
- 625-636.e5
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC7323595
- OpenAlex
- W2898490723
- Cited by
- 223
- References
- 51
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 30 · 2023: 32 · 2022: 28 · 2021: 44 · 2020: 28 · 2019: 12 · 2018: 1 · 2012: 1
- FWCI
- 16.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- NIH (R21 AI101777, T32 AI007538, T32 HLL007517)
- American Heart Association (#13POST16360006)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- mitochondria-derived vesicles, reactive oxygen species, hydrogen peroxide, phagosome, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, endoplasmic reticulum stress, IRE1α, Parkin, manganese superoxide dismutase, Toll-like receptor signaling, bacterial killing
- MeSH terms
- NADPH Oxidase 2, Superoxide Dismutase 2, PTEN-Induced Putative Kinase, Animals, Anti-Infective Agents, Anti-Bacterial Agents, Endoplasmic Reticulum, Endoribonucleases, Female, Hydrogen Peroxide, Macrophages, Male, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Phagosomes, Protein Kinases, Staphylococcal Infections, Staphylococcus aureus, Stress, Physiological, Superoxide Dismutase, Drug Delivery Systems, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Knockout, Ubiquitin-Protein Ligases, Microbial Viability, Toll-Like Receptors, Mice, Methicillin-Resistant Staphylococcus aureus
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