Advertisement

Journal of Medical Toxicology

, Volume 14, Issue 2, pp 144–151 | Cite as

Translational Application of Measuring Mitochondrial Functions in Blood Cells Obtained from Patients with Acute Poisoning

  • David H. JangEmail author
  • Utsha G. Khatri
  • Anita Mudan
  • Jennifer S. Love
  • Shawn Owiredu
  • David M. Eckmann
Preliminary Research

Abstract

It is conservatively estimated that 5,000 deaths per year and 20,000 injuries in the USA are due to poisonings caused by chemical exposures (e.g., carbon monoxide, cyanide, hydrogen sulfide, phosphides) that are cellular inhibitors. These chemical agents result in mitochondrial inhibition resulting in cardiac arrest and/or shock. These cellular inhibitors have multi-organ effects, but cardiovascular collapse is the primary cause of death marked by hypotension, lactic acidosis, and cardiac arrest. The mitochondria play a central role in cellular metabolism where oxygen consumption through the electron transport system is tightly coupled to ATP production and regulated by metabolic demands. There has been increasing use of human blood cells such as peripheral blood mononuclear cells and platelets, as surrogate markers of mitochondrial function in organs due to acute care illnesses. We demonstrate the clinical applicability of measuring mitochondrial bioenergetic and dynamic function in blood cells obtained from patients with acute poisoning using carbon monoxide poisoning as an illustration of our technique. Our methods have potential application to guide therapy and gauge severity of disease in poisoning related to cellular inhibitors of public health concern.

Keywords

Mitochondria Respiration Motility Carbon monoxide Toxicology Poisoning 

Notes

Sources of Funding

This work was funded by NIH grant K08HL136858 and the American College of Medical Toxicology (ACMT)-Medical Toxicology Foundation Research and Teaching Award (DJ) and Office of Naval Research grants N000141612100 and N000141712643 (DME).

Compliance with Ethical Standards

The University of Pennsylvania Institutional Review Board approved this study and informed consent was obtained from the patient or an appropriate surrogate.

Conflicts of Interest

None.

References

  1. 1.
    Watson C, Watson M, Kirk ST. Federal Funding for health security in FY2018. Health Secur. 2017;4:351–72.CrossRefGoogle Scholar
  2. 2.
    Jang DH, Shofer FS, Weiss SL, Becker LB. Impairment of mitochondrial respiration following ex vivo cyanide exposure in peripheral blood mononuclear cells. Clin Toxicol (Philadelphia, Pa). 2016;54:303–7.CrossRefGoogle Scholar
  3. 3.
    Lee SK, Rhee JS, Yum HS. Cyanide poisoning deaths detected at the national forensic service headquarters in seoul of Korea: a six year survey (2005~2010). Toxicol Res. 2012;28:195–9.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Anseeuw K, Delvau N, Burillo-Putze G, de Iaco F, Geldner G, Holmström P, et al. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med. 2013;20:2–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ, Andjelkovich DA. A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 1984;13:25–97.CrossRefPubMedGoogle Scholar
  6. 6.
    Truong DH, Eghbal MA, Hindmarsh W, Roth SH, O'Brien PJ. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab Rev. 2006;38:733–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Dadpour B, Mokhtarpour M, Abdollahi M, Afshari R. An outbreak of aluminium phosphide poisoning in Mashhad, Iran. Arhiv za higijenu rada i toksikologiju. 2016;67:65–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Etemadi-Aleagha A, Akhgari M, Iravani FS. Aluminum phosphide poisoning-related deaths in Tehran, Iran, 2006 to 2013. Medicine. 2015;94:e1637.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sciuto AM, Wong BJ, Martens ME, Hoard-Fruchey H, Perkins MW. Phosphine toxicity: a story of disrupted mitochondrial metabolism. Ann N Y Acad Sci. 2016;1374:41–51.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;30:105–16.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brown GC. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem J. 1992;284(Pt 1):1–13.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jang DH, Khatri UG, Shortal BP, et al. Alterations in mitochondrial respiration and reactive oxygen species in patients poisoned with carbon monoxide treated with hyperbaric oxygen. Intensive Care Med Exp. 2018;6:4.  https://doi.org/10.1186/s40635-018-0169-2.
  13. 13.
    Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, et al. Mitochondrial bioenergetics and structural network organization. J Cell Sci. 2007;120:838–48.CrossRefPubMedGoogle Scholar
  14. 14.
    Frederick RL, Shaw JM. Moving mitochondria: establishing distribution of an essential organelle. Traffic. 2007;8:1668–75.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Giedt RJ, Pfeiffer DR, Matzavinos A, Kao CY, Alevriadou BR. Mitochondrial dynamics and motility inside living vascular endothelial cells: role of bioenergetics. Ann Biomed Eng. 2012;40:1903–16.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Giedt RJ, Yang C, Zweier JL, Matzavinos A, Alevriadou BR. Mitochondrial fission in endothelial cells after simulated ischemia/reperfusion: role of nitric oxide and reactive oxygen species. Free Radic Biol Med. 2012;52:348–56.CrossRefPubMedGoogle Scholar
  17. 17.
    Balog J, Mehta SL, Vemuganti R. Mitochondrial fission and fusion in secondary brain damage after CNS insults. J Cereb Blood Flow Metab. 2016;36:2022–33.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rosdah AA, Holien JK, Delbridge LM, Dusting GJ, Lim SY. Mitochondrial fission - a drug target for cytoprotection or cytodestruction? Pharmacol Res Perspect. 2016;4:e00235.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jang DH, Greenwood JC, Spyres MB, Eckmann DM. Measurement of mitochondrial respiration and motility in acute care: sepsis, trauma, and poisoning. J Intensive Care Med. 2017;32:86–94.CrossRefPubMedGoogle Scholar
  20. 20.
    Callahan LA, Supinski GS. Sepsis induces diaphragm electron transport chain dysfunction and protein depletion. Am J Respir Crit Care Med. 2005;172:861–8.CrossRefPubMedGoogle Scholar
  21. 21.
    d'Avila JC, Santiago AP, Amancio RT, Galina A, Oliveira MF, Bozza FA. Sepsis induces brain mitochondrial dysfunction. Crit Care Med. 2008;36:1925–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Japiassu AM, Santiago AP, d'Avila JC, et al. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5′-triphosphate synthase activity. Crit Care Med. 2011;39:1056–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Karamercan MA, Weiss SL, Villarroel JP, et al. Can peripheral blood mononuclear cells be used as a proxy for mitochondrial dysfunction in vital organs during hemorrhagic shock and resuscitation? Shock (Augusta, Ga). 2013;40:476–84.CrossRefGoogle Scholar
  24. 24.
    Villarroel JP, Guan Y, Werlin E, Selak MA, Becker LB, Sims CA. Hemorrhagic shock and resuscitation are associated with peripheral blood mononuclear cell mitochondrial dysfunction and immunosuppression. J Trauma Acute Care Surg. 2013;75:24–31.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jang DH, Kelly M, Hardy K, Lambert DS, Shofer FS, Eckmann DM. A preliminary study in the alterations of mitochondrial respiration in patients with carbon monoxide poisoning measured in blood cells. Clin Toxicol (Philadelphia, Pa). 2017;55:579–84.CrossRefGoogle Scholar
  26. 26.
    Jang DH, Greenwood JC, Owiredu S, Ranganathan A, Eckmann DM. Mitochondrial networking in human blood cells with application in acute care illnesses. Mitochondrion. 2017.  https://doi.org/10.1016/j.mito.2017.12.009.
  27. 27.
    Chacko BK, Kramer PA, Ravi S, Johnson MS, Hardy RW, Ballinger SW, et al. Methods for defining distinct bioenergetic profiles in platelets, lymphocytes, monocytes, and neutrophils, and the oxidative burst from human blood. Lab Investig. 2013;93:690–700.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jang DH, Seeger SC, Grady ME, Shofer FS, Eckmann DM. Mitochondrial dynamics and respiration within cells with increased open pore cytoskeletal meshes. Biol Open. 2017;6:1831–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Barel O, Christine VMM, Ben-Zeev B, et al. Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain. 2017;140:568–81.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kandel J, Chou P, Eckmann DM. Automated detection of whole-cell mitochondrial motility and its dependence on cytoarchitectural integrity. Biotechnol Bioeng. 2015;112:1395–405.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, et al. The bioenergetic health index: a new concept in mitochondrial translational research. Clin Sci (London, England: 1979). 2014;127:367–73.CrossRefGoogle Scholar
  32. 32.
    Kramer PA, Chacko BK, Ravi S, Johnson MS, Mitchell T, Darley-Usmar VM. Bioenergetics and the oxidative burst: protocols for the isolation and evaluation of human leukocytes and platelets. J Vis Exp. 2014;85:e51301.  https://doi.org/10.3791/51301.
  33. 33.
    Ravi S, Mitchell T, Kramer P, Chacko B, Darley-Usmar VM. Mitochondria in monocytes and macrophages-implications for translational and basic research. Int J Biochem Cell Biol. 2014;53:202–7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Garrabou G, Inoriza JM, Moren C, et al. Mitochondrial injury in human acute carbon monoxide poisoning: the effect of oxygen treatment. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2011;29:32–51.CrossRefPubMedGoogle Scholar
  35. 35.
    Miro O, Alonso JR, Lopez S, Beato A, Casademont J, Cardellach F. Ex vivo analysis of mitochondrial function in patients attended in an emergency department due to carbon monoxide poisoning. Med Clin (Barc). 2004;122:401–6.CrossRefGoogle Scholar
  36. 36.
    Piel S, Ehinger JK, Elmer E, Hansson MJ. Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol (Oxford, England). 2015;213:171–80.CrossRefGoogle Scholar
  37. 37.
    Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P. Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev. 2011;67:103–18.CrossRefPubMedGoogle Scholar
  38. 38.
    Kramer PA, Chacko BK, George DJ, Zhi D, Wei CC, Dell’Italia LJ, et al. Decreased bioenergetic health index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients. Biosci Rep. 2015;35(4):e00237.  https://doi.org/10.1042/BSR20150161.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American College of Medical Toxicology 2018

Authors and Affiliations

  • David H. Jang
    • 1
    Email author
  • Utsha G. Khatri
    • 1
  • Anita Mudan
    • 1
  • Jennifer S. Love
    • 1
  • Shawn Owiredu
    • 1
  • David M. Eckmann
    • 2
    • 3
  1. 1.Department of Emergency Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Anesthesiology and Critical Care, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Bioengineering, School of Engineering and Applied SciencesUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations