Biology subjects

Fini, M. E.

Publications and source records attributed to Fini, M. E..

3 recordsLinked to original sources

bioRxiv2026

Targeting Mitochondrial Dysfunction with Mdivi-1 Confers Therapeutic Protection in a Mouse Model of Mustard Keratopathy

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.

biochemistry↗

bioRxiv2025

Clusterin reverses epitheliopathy, reduces inflammation, and restores goblet cells and corneal nerves in a mouse model of autoimmune dry eye

Chronic ocular surface disease (OSD) is characterized by corneal epitheliopathy, reduced barrier function and loss of nerves, accompanied by persistent inflammation. Current treatments offer limited relief and there is no approved therapy that promotes neurosensory regeneration in OSD. Here, we tested the therapeutic efficacy of clusterin (CLU), a molecular chaperone and MMP9 inhibitor found in tears, in Thbs1-deficient mice, a preclinical model of autoimmune dry eye associated with Sjogrens disease (SjD). These mice were treated topically at the ocular surface, bilaterally, for 3 weeks with recombinant human CLU (rhCLU) or human plasma-derived CLU (pCLU) eyedrops and compared to standard-of-care 0.1% dexamethasone eyedrops. Treatment with CLU significantly improved corneal barrier integrity, increased corneal nerve density, enhanced the proportion of corneal nerves with immunoreactivity for CGRP and promoted conjunctival goblet cell regeneration. Furthermore, CLU reduced immunoreactivity for ADAM17 in the corneal epithelium and reduced Tnfa expression in the conjunctiva, supporting its anti-inflammatory effect. Notably, all these effects were comparable to, or even exceeded, those resulting from treatment with dexamethasone. Based on its efficacy, we introduce CLU as a multifunctional and promising biotherapeutic for a widespread range of ocular inflammatory conditions involving corneal epitheliopathy and nerve loss, including dry eye associated with SjD.

immunology↗

bioRxiv2025

Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin

Familial mutations in myocilin cause vision loss in glaucoma due to misfolding and a toxic gain of function in a senescent cell type in the anterior eye. Here we characterize the cellular behavior and structure of the myocilin (myocilin A427T) mutant, of uncertain pathogenicity. Our characterization of A427T demonstrates that even mutations that minimally perturb myocilin structure and stability can present challenges for protein quality control clearance pathways. Namely, when expressed in an inducible immortalized trabecular meshwork cell line, inhibition of the proteasome reroutes wild-type myocilin, but not myocilin A427T, from endoplasmic reticulum associated degradation to lysosomal degradation. Yet, the crystal structure of the A427T myocilin olfactomedin domain shows modest perturbations largely confined to the mutation site. The previously unappreciated range of mutant myocilin behavior correlating with variable stability and structure provides a rationale for why it is challenging to predict causal pathogenicity of a given myocilin mutation, even in the presence of clinical data for members of an affected family. Comprehending the continuum of mutant myocilin behavior in the laboratory supports emerging efforts to use genetics to assess glaucoma risk in the clinic. In addition, the study supports a therapeutic strategy aimed at enhancing autophagic clearance of mutant myocilin. Significance statementO_LIRare familial mutations cause early onset glaucoma C_LIO_LIA427T is a case of uncertain pathogenicity C_LIO_LIA427T is structurally similar to wild-type but is not efficiently degraded C_LI

biochemistry↗