Differential inhibition of mitochondrial respiratory complexes by inhalation of combustion smoke and carbon monoxide, in vivo, in the rat brain

Abstract

Combustion smoke contains gases and particulates, which act via hypoxia and cytotoxicity producing mechanisms to injure cells and tissues. While carbon monoxide (CO) is the major toxicant in smoke, its toxicity is exacerbated in the presence of other compounds. Here, we examined modulations of mitochondrial and cytosolic energy metabolism by inhalation of combustion smoke versus CO, in vivo, in the rat brain. Measurements revealed reduced activities of respiratory chain (RC) complexes, with greater inhibition by smoke than equivalent CO in ambient air. In the case of RC complex IV, inhibition by CO and smoke was similar—suggesting that complex IV inhibition is primarily by the action of CO. In contrast, inhibition of complexes I and III was greater by smoke. Increases in cytosolic lactate dehydrogenase and pyruvate kinase activities accompanied inhibition of RC complexes, likely reflecting compensatory increases in cytosolic energy production. Together, the data provide new insights into the mechanisms of smoke inhalation-induced perturbations of brain energetics, which impact neuronal function and contribute to the development of neuropathologies in survivors of exposures to CO and combustion smoke.

Keywords::

• Brain
• combustion smoke
• carbon monoxide
• energetics
• mitochondria
• respiratory chain complexes

Acknowledgements

We thank Eileen Figueroa and Steve Schuenke for manuscript preparation.

Declaration of interest

This work was supported by National Institutes of Health grants ES014613 and NS039449 to EWE and Shriners Hospitals for Children grant SHG8670 to EWE. The funding organizations played no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.