The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Circulating mitochondrial DAMPs cause inflammatory responses to injury
Open accessAbstract
Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these organelles express biomolecules that resemble those expressed by prokaryotes, such as cardiolipin, double-stranded-hypomethylated DNA and N-formylated peptides12,13”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In human neutrophils, the binding of FPR1 and FPR2 to N-formylated peptides triggers the release of Ca2+ into the cytosol and ultimately leads to the migration and activation of neutrophils13”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mitochondria are considered as deriving from the endosymbiosis of an α-synfular; proteobacterium (3, 4), providing the organelles many bacterial features (3, 5–9).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cardiolipin, N-formylated peptides, mtDNA, ATP and reactive oxygen species are known mitochondrial damage-associated molecular patterns (9, 28–30).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [9]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Mitochondrial debris were observed in blood in the Twin Study (Garrett-Bakelman et al., 2019) and mitochondrial damage-associated molecular patterns (DAMPs) activate innate immune pathways (Banoth and Cassel, 2018; Zhang et al., 2010).”
From Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact (2020) · cites this paper as Zhang et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“In an extreme example such as massive trauma, mito-DAMPs, identified as mtDNA and formyl peptides, are acutely released from damaged tissues and cause a sepsis-like systemic inflammatory response syndrome by activating polymorphonuclear cells via TLR9 and formyl peptide receptor-129.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“Like bacteria, mitochondria are formed of an outer and an inner membrane (inner contains cardiolipin)4,5, express formylated peptides6,7, and contain a circular genome with hypomethylated DNA CpG motifs, referred to as mitochondrial DNA (mtDNA)8,9.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Mitochondria and their components (e.g. N-formylated peptides and mtDNA) are recognized as damage-associated molecular patterns (DAMPs), which activate the innate immune system and elicit an inflammatory response6,21–23.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [6]
In the citing paper
“MtDNA has been reported to activate immunity through two distinct pathways, namely Toll-like receptor 9 (TLR9; Zhang et al, 2010;Oka et al, 2012;Liu et al, 2015), and cGAS activation (White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Zhang et al, 2010
In the citing paper
“Mitochondria are a source of damage-associated molecular patterns (DAMPs), and among others, mtDNA has been shown to induce a pro-inflammatory state (Zhang et al, 2010;Oka et al, 2012;Wenceslau et al, 2014).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Zhang et al, 2010
In the citing paper
“MtDNA is recognized as foreign when found outside of mitochondria and can trigger inflammation (Maekawa et al., 2019; Shimada et al., 2012; Zhang et al., 2010).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhang et al., 2010
In the citing paper
“mtDNA is known to localize to endosomes”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhang et al., 2010
In the citing paper
“activate DNA sensor and pro-inflammatory mediator TLR9 (Zhang et al., 2010)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhang et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Baker, S. P., O’Neill, B., Haddon, W. F., & Long, W. B. (1974) · PubMed · Cited by 7,946
Mizgerd, J. P., Kubo, H., Kutkoski, G. J., Bhagwan, S. D., Scharffetter-Kochanek, K., Beaudet, A. L., & Doerschuk, C. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.8.1357 · Cited by 7,332
Baker, S. P., O’Neill, B., Haddon, W. F., & Long, W. B. (1974) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/00005373-197403000-00001 · Cited by 7,326
Tolerance, Danger, and the Extended Family
Matzinger, P. (1994) · Annual Review of Immunology · doi:10.1146/annurev.iy.12.040194.005015 · Cited by 4,848
Approaching the asymptote? Evolution and revolution in immunology.Preprint
Janeway, C. (1989) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1989.054.01.003 · Cited by 3,396
On the origin of mitosing cells
Sagan, L. (1967) · Journal of Theoretical Biology · doi:10.1016/0022-5193(67)90079-3 · Cited by 1,870
The mitochondrial genome: structure, transcription, translation and replication
Taanman, J.-W. (1999) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00161-3 · Cited by 1,635
Seong, S., & Matzinger, P. (2004) · Nature reviews. Immunology · doi:10.1038/nri1372 · Cited by 1,224
Toll-like receptors stimulate human neutrophil function
Hayashi, F., Means, T. K., & Luster, A. D. (2003) · Blood · doi:10.1182/blood-2003-04-1078 · Cited by 939
N-formylmethionyl peptides as chemoattractants for leucocytes.
Schiffmann, E., Corcoran, B. A., & Wahl, S. M. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.3.1059 · Cited by 889
Flagged first, then by citations
Cited by
Sorted by citations
Items 1,001–1,018 of 1,018
Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA
Becker, Y., Marcoux, G., Allaeys, I., Julien, A.-S., Loignon, R.-C., Benk-Fortin, H., Rollet-Labelle, E., Rauch, J., Fortin, P. R., & Boilard, E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01026 · Cited by 59
Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response
Bordt, E. A., Smith, C. J., Demarest, T. G., Bilbo, S. D., & Kingsbury, M. A. (2019) · Neurotoxicity Research · doi:10.1007/s12640-018-9962-7 · Cited by 58
Functions and regulation of lipocalin-2 in gut-origin sepsis: a narrative review
Lu, F., Inoue, K., Kato, J., Minamishima, S., & Morisaki, H. (2019) · Critical Care · doi:10.1186/s13054-019-2550-2 · Cited by 60
Duvvuri, B., Baddour, A. A., Deane, K. D., Feser, M. L., Nelson, J. L., Demoruelle, M. K., & Lood, C. (2021) · Journal of Autoimmunity · doi:10.1016/j.jaut.2021.102630 · Cited by 58
Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders
Adzic, M., Brkic, Z., Bulajic, S., Mitic, M., & Radojcic, M. B. (2016) · Drug Development Research · doi:10.1002/ddr.21332 · Cited by 60
Ebeling, M. C., Geng, Z., Kapphahn, R. J., Roehrich, H., Montezuma, S. R., Dutton, J. R., & Ferrington, D. A. (2021) · Cells · doi:10.3390/cells10040789 · Cited by 51
Murakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53
Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports
Zanini, G., De Gaetano, A., Selleri, V., Savino, G., Cossarizza, A., Pinti, M., Mattioli, A. V., & Nasi, M. (2021) · Cells · doi:10.3390/cells10102575 · Cited by 46
Chiappini, E., Bianconi, M., Dalzini, A., Petrara, M. R., Galli, L., Giaquinto, C., & De Rossi, A. (2018) · Aging · doi:10.18632/aging.101622 · Cited by 46
Marzetti, E., Guerra, F., Calvani, R., Marini, F., Biancolillo, A., Gervasoni, J., Primiano, A., Coelho-Júnior, H. J., Landi, F., Bernabei, R., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564417 · Cited by 45
Biomaterials-Driven Sterile Inflammation
Chen, H., Agrawal, D. K., & Thankam, F. G. (2022) · Tissue Engineering Part B: Reviews · doi:10.1089/ten.teb.2020.0253 · Cited by 41
Sialoside-based pattern recognitions discriminating infections from tissue injuries
Liu, Y., Chen, G.-Y., & Zheng, P. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.10.004 · Cited by 28
The conditional role of inflammation in pregnancy and cancer
Soeters, P. B., & Grimble, R. F. (2013) · Clinical Nutrition · doi:10.1016/j.clnu.2012.07.010 · Cited by 24
Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease
Lowes, H., Kurzawa-Akanbi, M., Pyle, A., & Hudson, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-72190-5 · Cited by 21
He, J., Lu, Y., Xia, H., Liang, Y., Wang, X., Bao, W., Yun, S., Ye, Y., Zheng, C., Liu, Z., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0124469 · Cited by 20
Cahill, T. J., Leo, V., Kelly, M., Stockenhuber, A., Kennedy, N. W., Bao, L., Cereghetti, G. M., Harper, A. R., Czibik, G., Liao, C., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.a115.665695 · Cited by 14
Zhang, Z., Qiu, X., Zeng, X., Liu, X., Lu, J., Xu, C., Huang, J., Zhao, C., & Zhan, Y. (2025) · Scientific Reports · doi:10.1038/s41598-025-18650-2 · Cited by 6
Dupanovic, M. (2015) · Encyclopedia of Trauma Care · doi:10.1007/978-3-642-29613-0_456
Metadata
- Authors
- Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K., & Hauser, C. J.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Queen Mary University of London (GB)
- Corresponding author
- Hauser, Carl J.
- ORCID
- Venue
- Nature
- Published
- 2010-03
- Volume
- 464
- Issue
- 7285
- Pages
- 104-107
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2843437
- OpenAlex
- W2134219545
- Cited by
- 3,812
- References
- 34
- Citations by year
- 2026: 253 · 2025: 254 · 2024: 268 · 2023: 266 · 2022: 267 · 2021: 294 · 2020: 275 · 2019: 243 · 2018: 246 · 2017: 252 · 2016: 248 · 2015: 230 · 2014: 196 · 2013: 176 · 2012: 148
- FWCI
- 70.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense
- National Institute of General Medical Sciences (R01GM051477, R01GM059179)
- Congressionally Directed Medical Research Programs
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Keywords
- mitochondrial DAMPs, mitochondrial damage-associated molecular patterns, mitochondrial DNA, formyl peptides, FPR1, TLR9, neutrophils, systemic inflammatory response syndrome, trauma (physical injury), innate immunity, neutrophil degranulation, MAPK signaling, target organ damage
- MeSH terms
- Animals, Cells, Cultured, DNA, Mitochondrial, Femur, Humans, Immunity, Innate, Liver, Male, Mitochondria, N-Formylmethionine Leucyl-Phenylalanine, Neutrophils, Phosphorylation, Wounds and Injuries, Rats, Sprague-Dawley, Muscle, Skeletal, Systemic Inflammatory Response Syndrome, Sepsis, CpG Islands, Calcium Signaling, Mitogen-Activated Protein Kinases, Receptors, Formyl Peptide, Fractures, Bone, Toll-Like Receptor 9, Rats, Acute Lung Injury
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
