Targeting Mitochondrial Dysfunction with Mdivi-1 Confers Therapeutic Protection in Cell Culture and Mouse Models of Mustard Keratopathy

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Abstract Mustard keratopathy, caused by exposure of the cornea to sulfur or nitrogen mustard vesicants, chemical warfare agents, can lead to severe and often irreversible vision loss. Despite considerable efforts to develop medical countermeasures, including anti-inflammatory, antioxidant, anti-fibrotic, and anti-angiogenic therapies, no treatment effectively targets the underlying mechanisms responsible for mustard-induced tissue injury or prevents long-term disease progression. In the present study, we comprehensively define mitochondrial mechanisms underlying nitrogen mustard-induced corneal injury in both our cell culture model in vitro and a mouse model in vivo. DNM1L (aka Drp1) is a mitochondria-localized dynamin-related GTPase that executes mitochondrial fission and facilitates the autophagic elimination of damaged mitochondrial components. Using complementary in vitro and in vivo models, we demonstrate that nitrogen mustard rapidly induces excessive mitochondrial fragmentation, bioenergetic collapse, membrane depolarization, oxidative stress, intracellular acidification, mitophagy, and apoptotic cell death. Pharmacological inhibition of DNM1L with Mdivi-1 preserves mitochondrial structure and function, restores cellular metabolism, reduces oxidative damage, and markedly improves corneal epithelial integrity, and tissue repair following nitrogen mustard exposure. Collectively, these findings establish mitochondrial dysfunction as a central pathological mechanism in mustard keratopathy and identify DNM1L-mediated mitochondrial remodeling as a therapeutically actionable target. The findings provide strong preclinical evidence supporting mitochondrial-directed therapy as a promising strategy for treating mustard keratopathy. This work was funded by: Project grant R01EY035220 (to MEF) from the National Eye Institute, National Institutes of Health, Bethesda, MD, USA A grant from the Massachusetts Lions Eye Research Foundation, Millis, MA, USA to the Department of Ophthalmology, Tufts University School of Medicine A challenge grant from Research to Prevent Blindness, Inc., New York, NY, USA to the Department of Ophthalmology, Tufts University School of Medicine One Sentence Summary The study findings establish mitochondrial dysfunction as a central pathological mechanism in mustard keratopathy and identify DNM1L-mediated mitochondrial remodeling as a therapeutically actionable target.

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