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Blood Cells as a Cellular Biomarker for Mitochondrial Function in a Experimental Model of Acute Carbon Monoxide Poisoning with Treatment
Journal article   Open access   Peer reviewed

Blood Cells as a Cellular Biomarker for Mitochondrial Function in a Experimental Model of Acute Carbon Monoxide Poisoning with Treatment

Devesh Bungatavula, John C Greenwood, Frances S Shofer, Guthrie Buehler, Shih-Han Kao, Matthew Kelly, Samuel S Shin, Johannes K Ehinger, Todd J Kilbaugh and David H Jang
Journal of medical toxicology, v 21(3), pp 327-335
01 Jul 2025
DOI: https://doi.org/10.1007/s13181-025-01077-6
PMID: 40295447
url
https://doi.org/10.1007/s13181-025-01077-6View
Published, Version of Record (VoR) Open

Abstract

Animals Biomarkers - blood Blood Cells - drug effects Blood Cells - metabolism Brain - drug effects Brain - metabolism Carbon Monoxide - toxicity Carbon Monoxide Poisoning - blood Carbon Monoxide Poisoning - drug therapy Carbon Monoxide Poisoning - metabolism Disease Models, Animal Dose-Response Relationship, Drug Male Mitochondria - drug effects Mitochondria - metabolism Prodrugs - pharmacology Rats Rats, Sprague-Dawley Succinates - pharmacology Succinates - therapeutic use
Carbon monoxide (CO) is a leading cause of environmental poisoning in the United States with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and mitochondrial dysfunction. Currently both biomarkers and therapies for CO poisoning are limited and require new approaches. Rats (~ 300 g) were divided into four groups of ten rodents per group (exposure): Control (room air), CO-400 (400 ppm), CO-1000 (1000 ppm) and CO-2000 (2000 ppm). Rodents received the assigned exposure through a secured tracheotomy tube over 120 min followed by 30 min of re-oxygenation at room air for a total of 150 min. Five additional rodents in each group were administered a succinate prodrug (NV354) at the start of exposure for the duration of the experiment until the reoxygenation period as separate experiments. Cortical brain tissue and whole blood were obtained for mitochondrial respiration. Stored plasma and snap frozen tissue stored at -80 C were used to obtain protein quantification with Western Blotting. All animals in the Sham, CO-400, and CO-1000 groups survived until the end of the exposure period; no animals in the CO-2000 groups survived the exposure and were counted as attrition. We observed a dose-dependent decrease in key respiratory states in both isolated brain mitochondria and peripheral blood mononuclear cells (PBMCs), and, PBMCs respiration more positively correlated with isolated brain mitochondria when compared to carboxyhemoglobin (COHb). There was no significant difference in mitochondrial respiratory states in animals treated with NV354 compared to the untreated group. The primary findings from this study include: (1) A dose-dependent decrease with key respiration states with higher concentrations of CO; (2) PBMCs had a higher correlation to isolated brain mitochondria respiration when compared to COHb; and (3) there was no treatment effect with the use of NV354.

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