Targeting Mitochondrial Dysfunction with Mdivi-1 Confers Therapeutic Protection in a Mouse Model of Mustard Keratopathy
- 1Tufts University School of Medicine
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. Our work provides strong preclinical evidence supporting mitochondrial-directed therapy as a promising strategy for treating mustard keratopathy.
Related
- The "Invisible Killer” of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies
- Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications
- Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury
- Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function.
- Impaired mitochondrial proteostasis underlies cardiomyocyte bioenergetic dysfunction in a murine 3-hit model of heart failure with preserved ejection fraction
BibTeX
@misc{mazumder2026targeting,
title = {{Targeting Mitochondrial Dysfunction with Mdivi-1 Confers Therapeutic Protection in a Mouse Model of Mustard Keratopathy}},
author = {A. Guha Mazumder and E. Magarychoff and H. Alemi and R. Raghav and M. T. Chin and C. D. Wiley and M. E. Fini},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.742467},
url = {https://www.biorxiv.org/content/10.64898/2026.08.27.742467v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeting Mitochondrial Dysfunction with Mdivi-1 Confers Therapeutic Protection in a Mouse Model of Mustard Keratopathy
AU - A. Guha Mazumder
AU - E. Magarychoff
AU - H. Alemi
AU - R. Raghav
AU - M. T. Chin
AU - C. D. Wiley
AU - M. E. Fini
PY - 2026
DA - 2026/08/27
PB - bioRxiv
DO - 10.64898/2026.08.27.742467
UR - https://www.biorxiv.org/content/10.64898/2026.08.27.742467v2
AB - 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. Our work provides strong preclinical evidence supporting mitochondrial-directed therapy as a promising strategy for treating mustard keratopathy.
ER -