Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema

Garcia Castro, C. F.; Balasubramanian Lakshmi, V. S.; Hadzic, S.; Nardiello, C.; Glaser, R. D.; Huttemann, M.; Grossman, L. I.; Kojonazarov, B.; Li, M.; Jash, S.; Koepke, J.; Gredic, M.; Wu, C.-Y.; Giordano, L.; Hecker, M.; Samakovlis, C.; Loku, E.; Cilic, A.; Better, J.; Matt, U.; Mueller, B.; Stieger, K.; Lytvynchuk, L.; Pervizaj-Oruqaj, L.; Guenther, A.; Wilhelm, J.; Herold, S.; Crnkovic, S.; Kwapiszewska, G.; Murphy, M. P.; Grimminger, F.; Bartkuhn, M.; Seeger, W.; Weissmann, N.; Pak, O.; Sommer, N.

doi:10.64898/2026.02.09.703513

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bioRxiv · 10.64898/2026.02.09.703513

Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic inflammation, emphysema, and mild pulmonary hypertension (PH). Oxidative/nitrosative stress are key drivers, but specific mitochondrial mechanisms remain unclear. We show increased expression of the regulatory mitochondrial cytochrome c oxidase subunit 4 isoform 2 (COX4I2) in an early murine model and human COPD. After 8 months of cigarette smoke exposure, Cox4i2-/- mice were completely protected from emphysema but not from PH, associated with reduced nitrosative stress, inflammation, and apoptosis. Using a novel Cox4i2 reporter mouse and in situ hybridization of human lungs, COX4I2 was detected in precapillary ACTA2+ cells and capillary pericytes. COX4I2 promotes mitochondrial reactive oxygen species (mtROS) production in these cells, thereby enhancing neutrophil migration and alveolar type II cell apoptosis, and modulates angiogenesis. In contrast to Cox4i2-/-, mitochondria-targeted antioxidant MitoQ reversed emphysema and PH, suggesting pericyte-specific regulation of COPD pathologies and mtROS inhibition as a therapeutic approach in COPD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/703513v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@83bca4org.highwire.dtl.DTLVardef@d5ebaborg.highwire.dtl.DTLVardef@632d1borg.highwire.dtl.DTLVardef@1267a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Garcia Castro, C. F., Balasubramanian Lakshmi, V. S., Hadzic, S., Nardiello, C., Glaser, R. D., Huttemann, M., Grossman, L. I., Kojonazarov, B., Li, M., Jash, S., Koepke, J., Gredic, M., Wu, C.-Y., Giordano, L., Hecker, M., Samakovlis, C., Loku, E., Cilic, A., Better, J., Matt, U., Mueller, B., Stieger, K., Lytvynchuk, L., Pervizaj-Oruqaj, L., Guenther, A., Wilhelm, J., Herold, S., Crnkovic, S., Kwapiszewska, G., Murphy, M. P., Grimminger, F., Bartkuhn, M., Seeger, W., Weissmann, N., Pak, O., Sommer, N.. 2026-02-09. Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema. https://doi.org/10.64898/2026.02.09.703513

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