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.
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
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?
Mitochondria express biomolecules resembling prokaryotic molecules, such as cardiolipin, double-stranded hypomethylated DNA and N-formylated peptides.
“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]
The paper’s Abstract says mitochondrial DNA resembles bacterial DNA in having nonmethylated CpG motifs and identifies mitochondrial formyl peptides as bacterial-like molecular signatures. It does not identify cardiolipin among those signatures or specify that the DNA is double-stranded; those details are not supported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn human neutrophils, FPR1 and FPR2 binding to N-formylated peptides triggers Ca2+ release and leads to neutrophil migration and activation.
“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]
The paper reports that formyl peptides signal through FPR1 and FPRL-1 and that human neutrophils respond to mitochondrial DAMPs with increased intracellular calcium, activation, and migration (Abstract; page not provided). But its experiments attribute these calcium and migration responses to FPR1: blocking FPR1 inhibits them, while an FPRL-1 control antibody has no effect on the calcium response. The copy therefore does not establish the claimed role for both receptors in that response. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMitochondria are considered to derive from endosymbiosis of an α-proteobacterium, providing the organelles many bacterial features.
“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]
The Abstract (page not supplied) describes mitochondria as bacterial-derived endosymbionts and identifies bacterial-like features, including formyl peptides and mtDNA motifs. Our copy does not specify that the bacterial ancestor was an α-proteobacterium. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCardiolipin, N-formylated peptides, mtDNA, ATP and reactive oxygen species are known mitochondrial damage-associated molecular patterns.
“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]
The Abstract (page unavailable) identifies N-formylated peptides and mtDNA as mitochondrial DAMPs. It does not identify cardiolipin or reactive oxygen species as such; it also reports that ATP was undetectable in the tested mitochondrial DAMP preparations and that removing ATP did not change their activity. Thus this source supports only part of the cited list. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMitochondrial debris were observed in blood in the Twin Study, and mitochondrial DAMPs activate innate immune pathways.
“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
In massive trauma, mito-DAMPs (mtDNA and formyl peptides) are acutely released from damaged tissues and cause sepsis-like systemic inflammatory response syndrome by activating polymorphonuclear cells via TLR9 and formyl peptide receptor-1.
“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]
Mitochondria express formylated peptides.
“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]
Mitochondria and their components, such as N-formylated peptides and mtDNA, are recognized as damage-associated molecular patterns that activate innate immunity and elicit inflammation.
“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]
mtDNA activates immunity through TLR9 and cGAS pathways.
“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
mtDNA can induce a pro-inflammatory state.
“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
mtDNA is recognized as foreign when outside mitochondria and can trigger inflammation.
“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
Mitochondrial DNA (mtDNA) localizes to endosomes.
“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
mtDNA activates the DNA sensor and pro-inflammatory mediator TLR9.
“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.
Cites
Baker, S. P., O’Neill, B., Haddon, W. F., & Long, W. B. (1974) · PubMed · Cited by 7,946 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Seong, S., & Matzinger, P. (2004) · Nature reviews. Immunology · doi:10.1038/nri1372 · Cited by 1,224 · see citing works
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 · see citing works
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 · see citing works
ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors
Chen, Y., Corriden, R., Inoue, Y., Yip, L., Hashiguchi, N., Zinkernagel, A. S., Nizet, V., Insel, P. A., & JUNGER, W. G. (2006) · Science · doi:10.1126/science.1132559 · Cited by 858 · see citing works
Self-citationNeutrophils and acute lung injury
Abraham, E. H. (2003) · Critical Care Medicine · doi:10.1097/01.ccm.0000057843.47705.e8 · Cited by 847 · see citing works
(2009) · PEDIATRICS · doi:10.1542/peds.2009-0257 · Cited by 800 · see citing works
Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses
Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I., & Tarkowski, A. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0703328 · Cited by 504 · see citing works
Toward an Epidemiology and Natural History of SIRS (Systemic Inflammatory Response Syndrome)
Bone, R. C. (1992) · JAMA · doi:10.1001/jama.1992.03490240060037 · Cited by 491 · see citing works
Gut Bacterial Translocation via the Portal Vein: A Clinical Perspective with Major Torso Trauma
MOORE, F. A., MOORE, E. E., POGGETTI, R., McANENA, O. J., PETERSON, V. M., ABERNATHY, C. M., & PARSONS, P. E. (1991) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/00005373-199105000-00006 · Cited by 491 · see citing works
Sasser, S. M., Hunt, R. C., Sullivent, E. E., Wald, M. M., Mitchko, J., Jurkovich, G. J., Henry, M. C., Salomone, J. P., Wang, S. C., Galli, R. L., et al. (2009) · PubMed · Cited by 420 · see citing works
Marcker, K. A., & Sanger, F. (1964) · Journal of Molecular Biology · doi:10.1016/s0022-2836(64)80164-9 · Cited by 353 · see citing works
Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes.
Uchida, K., Szweda, L. I., Chae, H. Z., & Stadtman, E. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8742 · Cited by 332 · see citing works
Guidelines for Field Triage of Injured Patients
McCoy, E., Chakravarthy, B., & Lotfipour, S. (2013) · Western Journal of Emergency Medicine · doi:10.5811/westjem.2013.1.15981 · Cited by 250 · see citing works
Edwin, A. D. (2006) · Frontiers in bioscience · doi:10.2741/1816 · Cited by 242 · see citing works
Matrix metalloproteinase-8: Cleavage can be decisive
VANLINT, P., & Libert, C. (2006) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2006.04.001 · Cited by 238 · see citing works
Pervasive CpG suppression in animal mitochondrial genomes
Cardon, L. R., Burge, C., Clayton, D. A., & Karlin, S. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.9.3799 · Cited by 238 · see citing works
Rabiet, M., Huet, E., & Boulay, F. (2005) · European Journal of Immunology · doi:10.1002/eji.200526338 · Cited by 218 · see citing works
The Bacterial Factor in Traumatic Shock
Fine, J., Frank, E. D., Ravin, H. A., Rutenberg, S. H., & SCHWEINBURG, F. B. (1959) · New England Journal of Medicine · doi:10.1056/nejm195901292600505 · Cited by 174 · see citing works
Wenzel‐Seifert, K., & Seifert, R. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.10.4591 · Cited by 115 · see citing works
PRECLINICAL MODELS OF TRAUMATIC, HEMORRHAGIC SHOCK
Hauser, C. J. (2005) · Shock · doi:10.1097/01.shk.0000191387.18818.43 · Cited by 93 · see citing works
Self-citationTarlowe, M. H., Kannan, K. B., Itagaki, K., Adams, J. M., Livingston, D. H., & Hauser, C. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.4.2066 · Cited by 60 · see citing works
Self-citationPAF-mediated Ca2+ influx in human neutrophils occurs via store-operated mechanisms
Hauser, C. J., Fekete, Z., Adams, J. M., Garced, M., Livingston, D. H., & Deitch, E. A. (2001) · Journal of Leukocyte Biology · doi:10.1189/jlb.69.1.63 · Cited by 48 · see citing works
Self-citationZhang, Q., Carter, E. A., Ma, B., White, M. F., Fischman, A. J., & Tompkins, R. G. (2005) · Life Sciences · doi:10.1016/j.lfs.2005.02.034 · Cited by 39 · see citing works
Self-citationMajor Trauma Enhances Store-Operated Calcium Influx in Human Neutrophils
Hauser, C. J., Fekete, Z., Livingston, D. H., Adams, J., Garced, M., & Deitch, E. A. (2000) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/00005373-200004000-00003 · Cited by 30 · see citing works
Self-citationINJURY-ENHANCED CALCIUM MOBILIZATION IN CIRCULATING RAT NEUTROPHILS MODELS HUMAN PMN RESPONSES
Fekete, Z., Hauser, C. J., Adams, J. M., Adams, C. A., Forsythe, R. M., Haskó, G., Xu, D.-Z., Livingston, D. H., & Deitch, E. A. (2001) · Shock · doi:10.1097/00024382-200116010-00003 · Cited by 21 · see citing works
Self-citationLee, S.-H., Lee, J., Kim, J., & Baek, S. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.10.111 · Cited by 15 · see citing works
West, M. A., Koons, A., Crandall, M. L., Skinner, R. A., Worley, M., & Shapiro, M. B. (2007) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/01.ta.0000259267.74789.9b · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
The NLRP3 inflammasome: molecular activation and regulation to therapeutics
Swanson, K. V., Deng, M., & Ting, J. P.-Y. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0165-0 · Cited by 4,884 · see citing works
IL‐6 in inflammation, immunity, and disease
Tanaka, T., Narazaki, M., & Kishimoto, T. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016295 · Cited by 5,046 · see citing works
Macrophages in Tissue Repair, Regeneration, and Fibrosis
Wynn, T. A., & Vannella, K. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.015 · Cited by 4,481 · see citing works
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · see citing works
Severe Sepsis and Septic Shock
Angus, D. C., & van der Poll, T. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1208623 · Cited by 3,993 · see citing works
Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
Franceschi, C., & Campisi, J. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu057 · Cited by 3,891 · see citing works
Inflammaging: a new immune–metabolic viewpoint for age-related diseases
Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0059-4 · Cited by 3,586 · see citing works
An overview of tissue and whole organ decellularization processes
Crapo, P. M., Gilbert, T. W., & Badylak, S. F. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.01.057 · Cited by 3,591 · see citing works
Immunogenic cell death and DAMPs in cancer therapy
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3380 · Cited by 3,223 · see citing works
Nakahira, K., Haspel, J. A., Rathinam, V. A. K., Lee, S.-J., Dolinay, T., Lam, H. C., Englert, J. A., Rabinovitch, M., Cernadas, M., Kim, H. P., et al. (2011) · Nature Immunology · doi:10.1038/ni.1980 · Cited by 3,049 · see citing works
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051 · see citing works
Neutrophils in the activation and regulation of innate and adaptive immunity
Mantovani, A., Cassatella, M. A., Costantini, C., & Jaillon, S. (2011) · Nature reviews. Immunology · doi:10.1038/nri3024 · Cited by 3,044 · see citing works
Gut microbiota functions: metabolism of nutrients and other food components
Rowland, I., Gibson, G., Heinken, A., Scott, K., Swann, J., Thiele, I., & Tuohy, K. (2018) · European Journal of Nutrition · doi:10.1007/s00394-017-1445-8 · Cited by 2,878 · see citing works
Molecular mechanisms of necroptosis: an ordered cellular explosion
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., & Kroemer, G. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2970 · Cited by 2,382 · see citing works
Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity
Griffith, J. W., Sokol, C. L., & Luster, A. D. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120145 · Cited by 2,044 · see citing works
Into the Eye of the Cytokine Storm
Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05015-11 · Cited by 1,940 · see citing works
DAMP-sensing receptors in sterile inflammation and inflammatory diseases
Gong, T., Liu, L., Jiang, W., & Zhou, R. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0215-7 · Cited by 1,672 · see citing works
Mechanisms of Cisplatin Nephrotoxicity
Miller, R. P., Tadagavadi, R. K., Ramesh, G., & Reeves, W. B. (2010) · Toxins · doi:10.3390/toxins2112490 · Cited by 1,635 · see citing works
The mitochondrial basis of aging
Sun, N., Youle, R. J., & Finkel, T. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.01.028 · Cited by 1,441 · see citing works
Necroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance
Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.003 · Cited by 1,411 · see citing works
Mitochondria in innate immune responses
West, A. P., Shadel, G. S., & Ghosh, S. (2011) · Nature Reviews Immunology · doi:10.1038/nri2975 · Cited by 1,376 · see citing works
The multifaceted functions of neutrophils
Mayadas, T. N., Cullere, X., & Lowell, C. A. (2014) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-164023 · Cited by 1,356 · see citing works
Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy
Zeiser, R., & Blazar, B. R. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1609337 · Cited by 1,316 · see citing works
Mitochondrial metabolism and cancer
Porporato, P. E., Filigheddu, N., Pedro, J. M. B., Kroemer, G., & Galluzzi, L. (2017) · Cell Research · doi:10.1038/cr.2017.155 · Cited by 1,292 · see citing works
PAMP s and DAMP s: signal 0s that spur autophagy and immunity
Tang, D., Kang, R., Coyne, C. B., Zeh, H. J., & Lotze, M. T. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01146.x · Cited by 1,250 · see citing works
A genomic storm in critically injured humans
Xiao, W., Mindrinos, M. N., Seok, J., Cuschieri, J., Cuenca, A. G., Gao, H., Hayden, D. L., Hennessy, L. V., Moore, E. E., Minei, J. P., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20111354 · Cited by 1,226 · see citing works
Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation
McDonald, B., Pittman, K., Menezes, G. B., Hirota, S. A., Slaba, I., Waterhouse, C. C. M., Beck, P. L., Muruve, D. A., & Kubes, P. (2010) · Science · doi:10.1126/science.1195491 · Cited by 1,210 · see citing works
Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure
Oka, T., Hikoso, S., Yamaguchi, O., Taneike, M., Takeda, T., Tamai, T., Oyabu, J., Murakawa, T., Nakayama, H., Nishida, K., et al. (2012) · Nature · doi:10.1038/nature10992 · Cited by 1,201 · see citing works
HIV Infection, Inflammation, Immunosenescence, and Aging
Deeks, S. G. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-042909-093756 · Cited by 1,349 · see citing works
Mitochondrial dysfunction: mechanisms and advances in therapy
Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,274 · see citing works
Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives
Roehlen, N., Crouchet, E., & Baumert, T. F. (2020) · Cells · doi:10.3390/cells9040875 · Cited by 1,237 · see citing works
Mitochondria are the powerhouses of immunity
Mills, E. L., Kelly, B., & O'Neill, L. A. J. (2017) · Nature Immunology · doi:10.1038/ni.3704 · Cited by 1,161 · see citing works
Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
Galluzzi, L., Vitale, I., Warren, S., Adjemian, S., Agostinis, P., Buqué, A., Chan, T. A.-T., Coukos, G., Demaria, S., Deutsch, É., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000337 · Cited by 1,151 · see citing works
Mitochondrial DNA in innate immune responses and inflammatory pathology
West, A. P., & Shadel, G. S. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.21 · Cited by 1,115 · see citing works
Pyroptosis versus necroptosis: similarities, differences, and crosstalk
Frank, D., & Vince, J. E. (2019) · Cell Death & Differentiation · doi:10.1038/s41418-018-0212-6 · Cited by 1,062 · see citing works
Immune surveillance by the liver
Jenne, C. N., & Kubes, P. (2013) · Nature Immunology · doi:10.1038/ni.2691 · Cited by 1,047 · see citing works
Neutrophil migration in infection and wound repair: going forward in reverse
de Oliveira, S., Rosowski, E. E., & Huttenlocher, A. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.49 · Cited by 1,058 · see citing works
Decoding cell death signals in liver inflammation
Brenner, C., Galluzzi, L., Kepp, O., & Kroemer, G. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.03.033 · Cited by 1,022 · see citing works
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Galluzzi, L., Bravo-San Pedro, J. M., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.137 · Cited by 1,002 · see citing works
Franceschi, C., Garagnani, P., Vitale, G., Capri, M., & Salvioli, S. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.09.005 · Cited by 997 · see citing works
Mitochondrial control of inflammation
Marchi, S., Guilbaud, E., Tait, S. W. G., Yamazaki, T., & Galluzzi, L. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00760-x · Cited by 1,027 · see citing works
Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis
Koupenova, M., Clancy, L., Corkrey, H. A., & Freedman, J. E. (2018) · Circulation Research · doi:10.1161/circresaha.117.310795 · Cited by 997 · see citing works
Mitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
Innate immunity in the central nervous system
Ransohoff, R. M., & Brown, M. A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58644 · Cited by 1,034 · see citing works
Mitochondrial dysfunction in pathophysiology of heart failure
Zhou, B., & Tian, R. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120849 · Cited by 934 · see citing works
Ong, S., Hernández‐Reséndiz, S., Crespo-Avilan, G. E., Талгатовна, М. Р., Kwek, X.-Y., Cabrera-Fuentes, H. A., & Hausenloy, D. J. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.01.001 · Cited by 925 · see citing works
An update on the regulatory mechanisms of NLRP3 inflammasome activation
Paik, S., Kim, J. K., Silwal, P., Sasakawa, C., & Jo, E. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00670-3 · Cited by 913 · see citing works
Acute Lung Injury: A Clinical and Molecular Review
Butt, Y. M., Kurdowska, A., & Allen, T. C. (2016) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2015-0519-ra · Cited by 898 · see citing works
Siti, H. N., Kamisah, Y., & Jaarin, K. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.03.005 · Cited by 898 · see citing works
The clearance of dead cells by efferocytosis
Boada-Romero, E., Martinez, J., Heckmann, B. L., & Green, D. R. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0232-1 · Cited by 893 · see citing works
Mitochondrial DNA in inflammation and immunity
Riley, J. S., & Tait, S. W. G. (2020) · EMBO Reports · doi:10.15252/embr.201949799 · Cited by 876 · see citing works
DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation
Zindel, J., & Kubes, P. (2019) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032847 · Cited by 874 · see citing works
Endogenous HMGB1 regulates autophagy
Tang, D., Kang, R., Livesey, K. M., Cheh, C.-W., Farkas, A., Loughran, P., Hoppe, G., Bianchi, M. E., Tracey, K. J., Zeh, H. J., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200911078 · Cited by 951 · see citing works
Salminen, A., Hyttinen, J. M. T., & Kaarniranta, K. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0748-0 · Cited by 866 · see citing works
The Chemokine System in Innate ImmunityPreprint
Sokol, C. L., & Luster, A. D. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016303 · Cited by 865 · see citing works
A new pathway for mitochondrial quality control: Mitochondrial-derived vesicles
Sugiura, A., McLelland, G., Fon, E. A., & McBride, H. M. (2014) · The EMBO Journal · doi:10.15252/embj.201488104 · Cited by 862 · see citing works
The systemic immune response to trauma: an overview of pathophysiology and treatment
Lord, J. M., Midwinter, M. J., Chen, Y., Belli, A., Brohi, K., Kovacs, E. J., Koenderman, L., Kubes, P., & Lilford, R. J. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60687-5 · Cited by 856 · see citing works
Self-citationXian, H., Watari, K., Sanchez-Lopez, E., Offenberger, J., Onyuru, J., Sampath, H., Ying, W., Hoffman, H. M., Shadel, G. S., & Karin, M. (2022) · Immunity · doi:10.1016/j.immuni.2022.06.007 · Cited by 850 · see citing works
Consensus guidelines for the detection of immunogenic cell death
Kepp, O., Senovilla, L., Vitale, I., Vacchelli, E., Adjemian, S., Agostinis, P., Apetoh, L., Aranda, F., Barnaba, V., Bloy, N., et al. (2014) · OncoImmunology · doi:10.4161/21624011.2014.955691 · Cited by 832 · see citing works
Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases
Mansouri, A., Gattolliat, C., & Asselah, T. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.06.083 · Cited by 817 · see citing works
Initiation and perpetuation of <scp>NLRP</scp> 3 inflammasome activation and assembly
Elliott, E. I., & Sutterwala, F. S. (2015) · Immunological Reviews · doi:10.1111/imr.12286 · Cited by 821 · see citing works
Pernas, L. F., & Scorrano, L. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105011 · Cited by 814 · see citing works
Origins, structures, and functions of circulating DNA in oncology
Thierry, A. R., El Messaoudi, S., Gahan, P. B., Anker, P., & Stroun, M. (2016) · Cancer and Metastasis Reviews · doi:10.1007/s10555-016-9629-x · Cited by 818 · see citing works
Immune cell regulation by autocrine purinergic signalling
JUNGER, W. G. (2011) · Nature reviews. Immunology · doi:10.1038/nri2938 · Cited by 813 · see citing works
Self-citationCannon, J. W. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1705649 · Cited by 794 · see citing works
The neutrophil in vascular inflammation
Phillipson, M., & Kubes, P. (2011) · Nature Medicine · doi:10.1038/nm.2514 · Cited by 766 · see citing works
McGill, M. R., Sharpe, M. R., Williams, C. D., Taha, M., Curry, S. C., & Jaeschke, H. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59755 · Cited by 764 · see citing works
Pattern Recognition Receptors and the Host Cell Death Molecular Machinery
Amarante-Mendes, G. P., Adjemian, S., Branco, L. M., Zanetti, L. C., Weinlich, R., & Bortoluci, K. R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02379 · Cited by 759 · see citing works
The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis.
Zheng, L.-L., Zhang, Z.-J., Sheng, P., & Mobasheri, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101249 · Cited by 717 · see citing works
Gentile, L. F., Cuenca, A. G., Efron, P. A., Ang, D., Bihorac, A., McKinley, B. A., Moldawer, L. L., & Moore, F. A. (2012) · Journal of Trauma and Acute Care Surgery · doi:10.1097/ta.0b013e318256e000 · Cited by 801 · see citing works
Mitochondria: master regulators of danger signalling
Galluzzi, L., Kepp, O., & Kroemer, G. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3479 · Cited by 733 · see citing works
The role of oxidative stress during inflammatory processes
Lugrin, J., Rosenblatt‐Velin, N., Parapanov, R., & Liaudet, L. (2013) · Biological Chemistry · doi:10.1515/hsz-2013-0241 · Cited by 742 · see citing works
Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline
Terrando, N., Monaco, C. G., Ma, D., Foxwell, B. M. J., Feldmann, M., & Maze, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014557107 · Cited by 730 · see citing works
Puga, I., Cols, M., Barra, C., He, B., Cassis, L., Gentile, M., Comerma, L., Chorny, A., Shan, M., Xu, W., et al. (2011) · Nature Immunology · doi:10.1038/ni.2194 · Cited by 731 · see citing works
Boudreau, L. H., Duchez, A.-C., Cloutier, N., Soulet, D., Martin, N., Bollinger, J., Paré, A., Rousseau, M., Naika, G. S., Lévesque, T., et al. (2014) · Blood · doi:10.1182/blood-2014-05-573543 · Cited by 703 · see citing works
Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation
Lü, Y., Li, Z., Zhang, S., Zhang, T., Liu, Y., & Zhang, L. (2023) · Theranostics · doi:10.7150/thno.79876 · Cited by 717 · see citing works
“tissue tearing and cell damage, which will result in the release of mitochondrial danger-associated molecular pattern (DAMP) molecules (such as mtDNA) into the blood of the host [110].”
BackgroundEmerging role of damage-associated molecular patterns derived from mitochondria in inflammation
Krysko, D. V., Agostinis, P., Krysko, O., Garg, A. D., Bachert, C., Lambrecht, B. N., & Vandenabeele, P. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.005 · Cited by 680 · see citing works
Chronic Heart Failure and Inflammation
Dick, S. A., & Epelman, S. (2016) · Circulation Research · doi:10.1161/circresaha.116.308030 · Cited by 691 · see citing works
Sepsis: Current Dogma and New Perspectives
Deutschman, C. S., & Tracey, K. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.04.001 · Cited by 676 · see citing works
Transcellular degradation of axonal mitochondria
Davis, C.-H. O., Kim, K.-Y., Bushong, E. A., Mills, E. A., Boassa, D., Shih, T., Kinebuchi, M., Phan, S., Zhou, Y., Bihlmeyer, N. A., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404651111 · Cited by 673 · see citing works
Sterile inflammation in the liver
Kubes, P., & Mehal, W. Z. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.09.008 · Cited by 666 · see citing works
Role of intestinal microbiota and metabolites on gut homeostasis and human diseases
Lin, L., & Zhang, J. (2017) · BMC Immunology · doi:10.1186/s12865-016-0187-3 · Cited by 731 · see citing works
Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and DiseasePreprint
Dc, W., & Chalkia, D. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021220 · Cited by 656 · see citing works
PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis
Bueno, M., Lai, Y.-C., Romero, Y., Brands, J., St. Croix, C. M., Kamga, C., Corey, C., Herazo-Maya, J. D., Sembrat, J., Lee, J. S., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci74942 · Cited by 627 · see citing works
Denning, N., Aziz, M., Gurien, S. D., & Wang, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02536 · Cited by 632 · see citing works
Methods of tissue decellularization used for preparation of biologic scaffolds and in vivo relevance
Keane, T. J., Swinehart, I. T., & Badylak, S. F. (2015) · Methods · doi:10.1016/j.ymeth.2015.03.005 · Cited by 670 · see citing works
Consequences of ineffective decellularization of biologic scaffolds on the host response
Keane, T. J., Londono, R., Turner, N. J., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2011.10.054 · Cited by 613 · see citing works
The role of mitochondrial dysfunction in sepsis-induced multi-organ failure
Singer, M. (2013) · Virulence · doi:10.4161/viru.26907 · Cited by 624 · see citing works
Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns
Schaefer, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.619304 · Cited by 618 · see citing works
Life and death of circulating cell-free DNA
Kustanovich, A., Schwartz, R., Peretz, T., & Grinshpun, A. (2019) · Cancer Biology & Therapy · doi:10.1080/15384047.2019.1598759 · Cited by 612 · see citing works
Mitochondria in health, disease, and aging
Harrington, J. S., Ryter, S. W., Plataki, M. E., Price, D. R., & Choi, A. M. K. (2023) · Physiological Reviews · doi:10.1152/physrev.00058.2021 · Cited by 622 · see citing works
Innate immune responses to trauma
Huber-Lang, M. S., Lambris, J. D., & Ward, P. A. (2018) · Nature Immunology · doi:10.1038/s41590-018-0064-8 · Cited by 604 · see citing works
Mitophagy, Mitochondrial Homeostasis, and Cell Fate
Ma, K., Chen, G., Li, W., Kepp, O., Zhu, Y., & Chen, Q. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00467 · Cited by 609 · see citing works
Disseminated intravascular coagulation
Gando, S., Levi, M. M., & Toh, C. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.37 · Cited by 598 · see citing works
Targeting Neutrophils in Ischemic Stroke: Translational Insights from Experimental Studies
Jickling, G. C., Liu, D., Ander, B. P., Stamova, B., Zhan, X., & Sharp, F. R. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.45 · Cited by 644 · see citing works
RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response Syndrome
Duprez, L., Takahashi, N., Hauwermeiren, F. V., Vandendriessche, B., Goossens, V., Berghe, T. V., Declercq, W., Libert, C., Cauwels, A., & Vandenabeele, P. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.020 · Cited by 591 · see citing works
Resolving postoperative neuroinflammation and cognitive decline
Terrando, N., Eriksson, L. I., Ryu, J. K., Yang, T., Monaco, C. G., Feldmann, M., Fagerlund, M. J., Charo, I. F., Akassoglou, K., & Maze, M. (2011) · Annals of Neurology · doi:10.1002/ana.22664 · Cited by 582 · see citing works
Klebsiella pneumoniae infection biology: living to counteract host defences
Bengoechea, J. A., & Sá‐Pessoa, J. (2018) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuy043 · Cited by 582 · see citing works
Johansson, P. I., Stensballe, J., Rasmussen, L. S., & Ostrowski, S. R. (2011) · Annals of Surgery · doi:10.1097/sla.0b013e318226113d · Cited by 554 · see citing works
- 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 › Epidemiology › 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
