Oxidative Injury to Lung Mitochondrial DNA is a Key Contributorfor the Development of Chemical Lung Injury

Dubey, S.; Yu, Z.; Stephens, E. M.; Lazrak, A.; Ahmad, I.; Aggarwal, S.; Andrabi, S.; Hossain, M. I.; Jilling, T.; Fernadez, S. R.; Bartels, J. L.; Lapi, S. E.; Mobley, J.; Pastukh, V. M.; Gillespie, M.; Matalon, S.

doi:10.1101/2024.11.22.624949

bioRxiv · 10.1101/2024.11.22.624949

Oxidative Injury to Lung Mitochondrial DNA is a Key Contributorfor the Development of Chemical Lung Injury

Dubey, S.·Yu, Z.·Stephens, E. M.·Lazrak, A.·Ahmad, I.·Aggarwal, S.·Andrabi, S.·Hossain, M. I.·Jilling, T.·Fernadez, S. R.·Bartels, J. L.·Lapi, S. E.·Mobley, J.·Pastukh, V. M.·Gillespie, M.·Matalon, S.

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Abstract

The mechanisms and extent to which inhalation of oxidant gases damage the mitochondrial genome contributing to the development of acute and chronic lung injury have not been investigated. C57BL/6 mice exposed to chlorine (Cl2) gas and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, significant oxidative injury to mtDNA, decreased intact lung mitochondrial (mt) DNA, generation of inflammatory pathway by DAMPs causing airway and alveolar injury with significant mortality. Global proteomics identified over 1400 lung proteins with alteration of key mitochondrial proteins at 24 h post Cl2 exposure. Intranasal instillation of a recombinant protein containing mitochondrial targeted OGG1 (mitoOGG1) post exposure, decreased oxidative injury to mtDNA, lung mitochondrial proteome, severity of the acute and chronic lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury.

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Dubey, S., Yu, Z., Stephens, E. M., Lazrak, A., Ahmad, I., Aggarwal, S., Andrabi, S., Hossain, M. I., Jilling, T., Fernadez, S. R., Bartels, J. L., Lapi, S. E., Mobley, J., Pastukh, V. M., Gillespie, M., Matalon, S.. 2024-11-25. Oxidative Injury to Lung Mitochondrial DNA is a Key Contributorfor the Development of Chemical Lung Injury. https://doi.org/10.1101/2024.11.22.624949

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