Skip to main content
SpringerLink
Log in

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

  • Preliminary Research
  • Published:
Journal of Medical Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Watson C, Watson M, Kirk ST. Federal Funding for health security in FY2018. Health Secur. 2017;4:351–72.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Etemadi-Aleagha A, Akhgari M, Iravani FS. Aluminum phosphide poisoning-related deaths in Tehran, Iran, 2006 to 2013. Medicine. 2015;94:e1637.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;30:105–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Brown GC. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem J. 1992;284(Pt 1):1–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Frederick RL, Shaw JM. Moving mitochondria: establishing distribution of an essential organelle. Traffic. 2007;8:1668–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA

    David H. Jang, Utsha G. Khatri, Anita Mudan, Jennifer S. Love & Shawn Owiredu

  2. Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David M. Eckmann

  3. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David M. Eckmann

Authors
  1. David H. Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Utsha G. Khatri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anita Mudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer S. Love
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shawn Owiredu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David M. Eckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David H. Jang.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jang, D.H., Khatri, U.G., Mudan, A. et al. Translational Application of Measuring Mitochondrial Functions in Blood Cells Obtained from Patients with Acute Poisoning. J. Med. Toxicol. 14, 144–151 (2018). https://doi.org/10.1007/s13181-018-0656-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13181-018-0656-6

Keywords

Search

Navigation