Kesavan, K. | bioRxiv Science

bioRxiv2025

Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma and ex-vivo human retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/638142v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1620793org.highwire.dtl.DTLVardef@df5a25org.highwire.dtl.DTLVardef@1974c34org.highwire.dtl.DTLVardef@bf605_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

neuroscience↗

bioRxiv2023

Vicious cycle of hemodynamic perturbation and endothelial injury in development and progression of pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a devastating disease caused by loss of effective lung microvasculature for which there is no curative treatment. Evidence from preclinical models and human disease-causing genetic mutations point to endothelial cell (EC) injury and apoptosis as a central trigger for the initiation of PAH. However, how EC apoptosis leads to pulmonary hypertension (PH) and complex arteriolar remodeling is uncertain. MethodsRats were subjected to SU5416-hypoxia (SUHx) and EC apoptosis, pulmonary vascular remodeling and arterial volume was assessed by immunohistochemistry, histology and microCT, respectively. Left pulmonary artery banding (LPAB) was performed, either 1 week before (prevention) or 5 weeks after SU injection (reversal), to study the effect of hemodynamic offloading. ResultsIn the SUHx model, EC apoptosis was markedly increased as early as 3 days post-SU, persisting through PAH development, and this was associated with a profound arterial pruning with reduction in lung arterial volume ([~]80%). LPAB abrogated lung EC apoptosis in the banded left lung and prevented as well as reversed arteriolar pruning. Moreover, in the reversal protocol, removal of the band at 10 weeks resulted in improvement in pulmonary hemodynamics and RV function at 13 weeks. ConclusionThese data demonstrate that perturbed hemodynamic factors triggered by lung microvascular arteriolar loss play a requisite role in perpetuating endothelial injury in experimental PAH, leading to persistent arterial EC injury and disease progression. Importantly, vascular loss, arterial remodeling and PH are reversible once the cycle of perturbed hemodynamics and EC injury is broken by unilateral lung banding.

physiology↗