Sepsis induces brain mitochondrial dysfunction.
Open accessAbstract
OBJECTIVE: Mitochondrial dysfunctions have been associated with the pathogenesis of sepsis. A systematic survey of mitochondrial function in brain tissues during sepsis is lacking. In the present work, we investigate brain mitochondrial function in a septic mouse model. DESIGN: Prospective animal study. SETTING: University research laboratory. SUBJECTS: Male Swiss mice, aged 6-8 wks. INTERVENTIONS: Mice were subjected to cecal ligation and perforation (sepsis group) with saline resuscitation or to sham operation (control group). MEASUREMENTS AND MAIN RESULTS: Oxygen consumption was measured polarographically in an oximeter. Brain homogenates from septic animals presented higher oxygen consumption in the absence of adenosine 5'-diphosphate (state 4) compared with control animals. The increase in state 4 respiration in animals in the cecal ligation and perforation group resulted in a drastic decrease in both respiratory control and adenosine 5'-diphosphate/oxygen ratios, indicating a reduction in the oxidative phosphorylation efficiency. Septic animals presented a significant increase in the recovery time of mitochondrial membrane potential on adenosine 5'-diphosphate addition compared with control animals, suggesting a proton leak through the inner mitochondrial membrane. The septic group presented a general reduction in the content of cytochromes. Moreover, the activity of cytochrome c oxidase was specifically and significantly decreased in the brain during sepsis. Hydrogen peroxide generation by brain mitochondria from septic mice did not respond to substrates of electron transport chain or to adenosine 5'-diphosphate, showing that mitochondrial function may be compromised in a critical level in the brain during sepsis. CONCLUSIONS: The mitochondrial dysfunctions demonstrated here indicate that uncoupling of oxidative phosphorylation takes place in the brain of septic mice, compromising tissue bioenergetic efficiency.
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?
Chronic impairments of neuronal metabolism would be expected to compromise brain function and contribute to brain pathology.
“For the same reason, chronic impairments of neuronal metabolism would be expected to compromise brain function and contribute to brain pathology, which may be the case in epilepsy (due to runaway excitatory activity or directly to metabolic disorders [57]), sepsis [58], mitochondrial disorders, which strongly affect the brain [59], and Alzheimer's disease [60].”
From Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution (2011) · cites this paper as [58]
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
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Early goal-directed therapy in the treatment of severe sepsis and septic shock
Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., & Tomlanovich, M. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010307 · Cited by 10,743 · see citing works
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455 · see citing works
Boveris, A., & Chance, B. (1973) · Biochemical Journal · doi:10.1042/bj1340707 · Cited by 2,626 · see citing works
Oxidative stress and neurodegeneration: where are we now?
Halliwell, B. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03907.x · Cited by 2,614 · see citing works
Korshunov, S. S., Skulachev, V. P., & Starkov, A. A. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01159-9 · Cited by 1,727 · see citing works
Association between mitochondrial dysfunction and severity and outcome of septic shock
Brealey, D. A., Brand, M. P., Hargreaves, I. P., Heales, S., Land, J. M., Smolenski, R. T., Davies, N. A., Cooper, C. E., & Singer, M. (2002) · The Lancet · doi:10.1016/s0140-6736(02)09459-x · Cited by 1,505 · see citing works
A Trial of Goal-Oriented Hemodynamic Therapy in Critically Ill Patients
Gattinoni, L., Brazzi, L., Pelosi, P. P., Latini, R., Tognoni, G., Pesenti, A. M., & Fumagalli, R. (1995) · New England Journal of Medicine · doi:10.1056/nejm199510193331601 · Cited by 1,486 · see citing works
RESPIRATORY ENZYMES IN OXIDATIVE PHOSPHORYLATION
Chance, B., & Williams, G. R. (1955) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)57189-7 · Cited by 1,473 · see citing works
Superoxide activates mitochondrial uncoupling proteins
Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., Harper, J. A., Roebuck, S. J., Morrison, A., Pickering, S., et al. (2002) · Nature · doi:10.1038/415096a · Cited by 1,382 · see citing works
Clementi, E., Brown, G. C., Feelisch, M., & Moncada, S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7631 · Cited by 863 · see citing works
Mitochondrial permeability transition and oxidative stress
Kowaltowski, A. J., Castilho, R. F., & Vercesi, A. E. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02316-x · Cited by 832 · see citing works
Safranine as a probe of the mitochondrial membrane potential
Åkerman, K. E. O., & Wikström, M. K. F. (1976) · FEBS Letters · doi:10.1016/0014-5793(76)80434-6 · Cited by 793 · see citing works
Differential Inhibitory Action of Nitric Oxide and Peroxynitrite on Mitochondrial Electron Transport
Cassina, A., & Radí, R. (1996) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1996.0178 · Cited by 725 · see citing works
A signalling role for 4‐hydroxy‐2‐nonenal in regulation of mitochondrial uncoupling
Echtay, K. S., Esteves, T. C., Pakay, J. L., Jekabsons, M. B., Lambert, A. J., Portero‐Otín, M., Pamplona, R., Vidal‐Puig, A. J., Wang, S., Roebuck, S. J., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg412 · Cited by 597 · see citing works
Nitric oxide, cell bioenergetics and neurodegeneration
Moncada, S., & Bolaños, J. P. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03988.x · Cited by 556 · see citing works
Meta-analysis of hemodynamic optimization in high-risk patients*
Kern, J. W., & Shoemaker, W. C. (2002) · Critical Care Medicine · doi:10.1097/00003246-200208000-00002 · Cited by 550 · see citing works
Baker, C. C., Chaudry, I. H., Gaines, H. O., & Baue, A. E. (1983) · PubMed · Cited by 506 · see citing works
Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure
Brealey, D. A., Karyampudi, S., Jacques, T. S., Novelli, M. R., Stidwill, R. P., Taylor, V., Smolenski, R. T., & Singer, M. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00432.2003 · Cited by 461 · see citing works
Vanhorebeek, I., Vos, R. D., Mesotten, D., Wouters, P. J., Wolf‐Peeters, C. D., & den Berghe, G. V. (2005) · The Lancet · doi:10.1016/s0140-6736(04)17665-4 · Cited by 450 · see citing works
The Spectrum of Septic Encephalopathy
Eidelman, L. A. (1996) · JAMA · doi:10.1001/jama.1996.03530300054040 · Cited by 440 · see citing works
Impact of encephalopathy on mortality in the sepsis syndrome
Sprung, C. L., Peduzzi, P. N., Shatney, C. H., Schein, R. M. H., Wilson, M. F., Sheagren, J. N., & Hinshaw, L. B. (1990) · Critical Care Medicine · doi:10.1097/00003246-199008000-00001 · Cited by 426 · see citing works
Sims, N. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb04189.x · Cited by 388 · see citing works
The Neuropathology of Septic Shock
Sharshar, T., Annane, D., de la Gradmaison, G. L., Brouland, J. P., Hopkinson, N. S., & Gray, F. (2004) · Brain Pathology · doi:10.1111/j.1750-3639.2004.tb00494.x · Cited by 348 · see citing works
Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome
Crouser, E. D. (2004) · Mitochondrion · doi:10.1016/j.mito.2004.07.023 · Cited by 322 · see citing works
Mitochondrial Oxygen Affinity, Respiratory Flux Control And Excess Capacity Of Cytochrome c Oxidase
Gnaiger, E., Lassnig, B., Kuznetsov, A. V., Rieger, G. E., & Margreiter, R. (1998) · Journal of Experimental Biology · doi:10.1242/jeb.201.8.1129 · Cited by 318 · see citing works
Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging
Navarro, A., & Boveris, A. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00226.2004 · Cited by 309 · see citing works
Fink, M. P. (2001) · Critical Care Clinics · doi:10.1016/s0749-0704(05)70161-5 · Cited by 302 · see citing works
Ebersoldt, M., Sharshar, T., & Annane, D. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0622-2 · Cited by 292 · see citing works
Galdo, N. A. R., Clementi, E., Melani, M., Boveris, A., Cadenas, E., Moncada, S., & Poderoso, J. J. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590139 · Cited by 278 · see citing works
RIOBÓ, N. A., CLEMENTI, E., MELANI, M., BOVERIS, A., CADENAS, E., MONCADA, S., & PODEROSO, J. J. (2001) · Biochemical Journal · doi:10.1042/bj3590139 · Cited by 278 · see citing works
Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity
Crouser, E. D., JULIAN, M. W., Blaho, D. V., & Pfeiffer, D. R. (2002) · Critical Care Medicine · doi:10.1097/00003246-200202000-00002 · Cited by 277 · see citing works
Nitric oxide-mediated mitochondrial damage: A potential neuroprotective role for glutathione
Bolaños, J. P., Heales, S. J. R., Peuchen, S., Barker, J. E., Land, J. M., & Clark, J. B. (1996) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00240-7 · Cited by 263 · see citing works
Votyakova, T. V., & Reynolds, I. J. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2004.07.025 · Cited by 207 · see citing works
Mitochondrial Membrane Potential and Apoptosis Peripheral Blood Monocytes in Severe Human Sepsis
Adrie, C., Bachelet, M., Vayssier‐Taussat, M., Russo‐Marie, F., Bouchaert, I., Adib‐Conquy, M., Cavaillon, J., Pinsky, M. R., Dhainaut, J.-F., & Polla, B. S. (2001) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.164.3.2009088 · Cited by 205 · see citing works
Endogenous peroxynitrite mediates mitochondrial dysfunction in rat diaphragm during endotoxemia
Boczkowski, J., Lisdero, C. L., Lanone, S., Samb, A., Carreras, M. C., Boveris, A., Aubier, M., & Poderoso, J. J. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.12.1637 · Cited by 179 · see citing works
Gegg, M. E., Beltrán, B., Salas-Pino, S., Bolaños, J. P., Clark, J. B., Moncada, S., & Heales, S. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01821.x · Cited by 168 · see citing works
Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation
Barichello, T., Fortunato, J. J., Vitali, Â. M., Feier, G., Reinke, A., Moreira, J. C. F., Quevedo, J., & Dal‐Pizzol, F. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000201880.50116.12 · Cited by 160 · see citing works
Oxygen transport patterns in patients with sepsis syndrome or septic shock
Hayes, M., Timmins, A. C., Yau, E. H. S., Palazzo, M. G. A., Watson, D. I., & Hinds, C. (1997) · Critical Care Medicine · doi:10.1097/00003246-199706000-00007 · Cited by 157 · see citing works
Cognitive impairment in sepsis survivors from cecal ligation and perforation*
Barichello, T., Martins, M. R., Reinke, A., Feier, G., Ritter, C., Quevedo, J., & Dal‐Pizzol, F. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000150741.12906.bd · Cited by 140 · see citing works
The kinetic basis of threshold effects observed in mitochondrial diseases: a systemic approach
Letellier, T., Heinrich, R., Malgat, M., & Mazat, J. (1994) · Biochemical Journal · doi:10.1042/bj3020171 · Cited by 134 · see citing works
Inhibition of cellular respiration by endogenously produced carbon monoxide
D’Amico, G., Lam, F., Hagen, T., & Moncada, S. (2006) · Journal of Cell Science · doi:10.1242/jcs.02914 · Cited by 132 · see citing works
Protti, A., & Singer, M. (2006) · Critical Care · doi:10.1186/cc5014 · Cited by 126 · see citing works
Sepsis Induces Diaphragm Electron Transport Chain Dysfunction and Protein Depletion
Callahan, L. A., & Supinski, G. S. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200410-1344oc · Cited by 111 · see citing works
Barker, J. E., Heales, S., Cassidy, A., Bolaños, J. P., Land, J. M., & Clark, J. B. (1996) · Brain Research · doi:10.1016/0006-8993(96)00003-0 · Cited by 109 · see citing works
Antibiotic Treatment in a Murine Model of Sepsis: Impact on Cytokines and Endotoxin Release
Vianna, R. C. S., Gomes, R. N., Bozza, F. A., et al. (2004) · Shock · doi:10.1097/01.shk.0000111828.07309.26 · Cited by 106 · see citing works
Self-citationEffect of Endotoxemia on Liver Cell Mitochondria in Man
SCHUMER, W., Gupta, T. K. D., Moss, G. S., & Nyhus, L. M. (1970) · Annals of Surgery · doi:10.1097/00000658-197006010-00008 · Cited by 104 · see citing works
Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function
Porta, F., Takala, J. A., Weikert, C., Bracht, H., Kolarova, A., Lauterburg, B. H., Borotto, E. E., & Jakob, S. M. (2006) · Critical Care · doi:10.1186/cc5013 · Cited by 91 · see citing works
Antibiotic treatment in a murine model of sepsis: impact on cytokines and endotoxin release.
Vianna, R. C. S., Gomes, R. N., Bozza, F. A., et al. (2004) · PubMed · doi:10.1097/01.shk.0000111828.07309.21 · Cited by 83 · see citing works
Self-citationFink, M. P., & Evans, T. W. (2001) · Intensive Care Medicine · doi:10.1007/s00134-001-1205-2 · Cited by 76 · see citing works
Expression of Classical Mitochondrial Respiratory Responses in Homogenates of Rat Forebrain
Sims, N. R., & Blass, J. P. (1986) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1986.tb04529.x · Cited by 62 · see citing works
Chuang, Y., Tsai, J.-L., Chang, A. Y., Chan, J. Y. H., Liou, C.-W., & Chan, S. H. H. (2002) · Journal of Biomedical Science · doi:10.1007/bf02254981 · Cited by 57 · see citing works
Kadoi, Y., & Goto, F. (2004) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000118111.94913.22 · Cited by 51 · see citing works
Chuang, Y., Tsai, J.-L., Chang, A. Y., et al. (2002) · Journal of Biomedical Science · doi:10.1159/000064727 · Cited by 49 · see citing works
Milbrandt, E. B., & Angus, D. C. (2006) · Critical Care · doi:10.1186/cc5078 · Cited by 41 · see citing works
Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis
Sun, X., Wray, C., Tian, X., Hasselgren, P.-O., & Lu, J. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00446.2002 · Cited by 36 · see citing works
Fink, M. P. (2002) · Intensive Care Medicine · doi:10.1007/s00134-001-1191-4 · Cited by 18 · see citing works
Effect of endotoxin, dobutamine and dopamine on muscle mitochondrial respiration in vitro
Porta, F., Takala, J. A., Weikert, C., et al. (2006) · Journal of Endotoxin Research · doi:10.1179/096805106x153952 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Vianna RC, Gomes RN, Bozza FA, et al: An- tibiotic treatment in a murine model of sep- sis: Impact on cytokines and endotoxin re- lease. Shock 2004; 21:115-120
- Nicholls DG, Ferguson SJ: Bioenergetics 3. Third Edition. London, Academic Press, 2002
- Kowaltowski AJ, Castilho RF, Vercesi AE: Mi- tochondrial permeability transition and oxi- dative stress. FEBS Lett 2001; 495:12-15
Cited by
Sorted by citations
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
Sepsis-associated encephalopathy
Gofton, T. E., & Young, G. B. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.183 · Cited by 821 · see citing works
Sankowski, R., Mader, S., & Valdés-Ferrer, S. I. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00028 · Cited by 351 · see citing works
Herculano-Houzel, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017514 · Cited by 343 · see citing works
Characterization of Sepsis and Sepsis-Associated Encephalopathy
Feng, Q., Ai, Y.-H., Gong, H., Wu, L., Ai, M.-L., Deng, S.-Y., Huang, L., Peng, Q.-Y., & Zhang, L.-N. (2019) · Journal of Intensive Care Medicine · doi:10.1177/0885066617719750 · Cited by 101 · see citing works
Ehler, J., Barrett, L. K., Taylor, V., Groves, M., Scaravilli, F., Wittstock, M., Kolbaske, S., Grossmann, A., Henschel, J., Gloger, M., et al. (2017) · Critical Care · doi:10.1186/s13054-017-1850-7 · Cited by 80 · see citing works
Zhao, P., Li, X., Yang, Q., Lu, Y., Wang, G., Yang, H., Dong, J., & Zhang, H. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1038802 · Cited by 43 · see citing works
Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis
Kobayashi, T., Uchino, H., Elmér, E., Ogihara, Y., Fujita, H., Sekine, S., Ishida, Y., Saiki, I., Shibata, S., & Kawachi, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020961 · Cited by 22 · see citing works
- Authors
- d’Avila, J. D. C. P., Santiago, A. P. S. A., Amâncio, R. T., Galina, A., Oliveira, M. F., & Bozza, F. A.
- Affiliations
- Universidade Federal do Rio de Janeiro (BR)
- Venue
- Critical Care Medicine
- Published
- 2008-06
- Volume
- 36
- Issue
- 6
- Pages
- 1925-1932
- ISSN
- 0090-3493 (ISSN-L)
- OpenAlex
- W2079481041
- Cited by
- 134
- References
- 58
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 3 · 2019: 8 · 2018: 11 · 2017: 12 · 2016: 5 · 2015: 11 · 2014: 8 · 2013: 10 · 2012: 6
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.arca.fiocruz.br
- Licence
- other-oa
- Locations
- Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Ministério da Saúde
- Fundação Oswaldo Cruz
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- sepsis, mitochondrial uncoupling, state 4 respiration, mitochondrial membrane potential, cytochrome c oxidase, cytochrome content, hydrogen peroxide production, brain energy metabolism, cecal ligation and puncture, mitochondrial bioenergetics
- MeSH terms
- Adenosine Diphosphate, Animals, Brain, Electron Transport Complex IV, Disease Models, Animal, Electron Transport, Energy Metabolism, Hydrogen Peroxide, Male, Mitochondria, Oxidative Phosphorylation, Oxygen Consumption, Sepsis, Mitochondrial Diseases, Mitochondrial Membranes, Mice
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
