Wednesday, March 19, 2025
3/19/2025
Abstract Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Elevated intraocular pressure (IOP) due to dysfunction of trabecular meshwork (TM) tissue is a hallmark of POAG. However, the pathological mechanisms leading to TM dysfunction and IOP elevation are poorly understood. Our recent studies have shown that chronic endoplasmic reticulum (ER) stress is associated with the pathophysiology of glaucomatous TM damage and IOP elevation. However, the exact mechanisms of TM cell dysfunction/loss are not completely understood. The ER and mitochondria communicate constantly via mitochondria-associated ER membranes (MAMs) to regulate vital cellular functions including autophagy. Autophagy degrades long-lived proteins and damaged organelles including mitochondria (known as mitophagy) via lysosomes. Impaired mitophagy is known to cause abnormal accumulation of damaged mitochondria resulting into cell death. In our preliminary studies, primary human TM cells exhibited an abundant mitochondria and MAMs. Interestingly, human primary TM cells and TM tissues from POAG donor eyes demonstrated increased accumulation of mitochondria. Moreover, chronic ER stress-induced transcriptional factors, ATF4 and CHOP led to increased reactive oxygen species and impaired mitophagy in primary human TM cells. Our overall goals are to define the role of MAMs and impaired mitophagy in TM dysfunction and IOP elevation in POAG and to further target these pathways for the treatment of glaucoma. We hypothesize that chronic ER stress induces impaired mitophagy and mitochondrial dysfunction, leading to TM dysfunction/loss and IOP elevation in POAG. We will determine whether impaired mitophagy and mitochondrial dysfunction are associated with TM dysfunction and IOP elevation in human and mouse glaucoma (Aim 1). We will further determine whether chronic ER stress induces impaired mitophagy and mitochondrial dysfunction, leading to TM dysfunction/loss and IOP elevation (Aim 2). Finally, we will perform proof-of-principle studies exploring whether the mitophagy enhancers improve outflow facility and reduce elevated IOP in mouse models of glaucoma (Aim 3). We will utilize human primary TM cells and post-mortem TM tissues from normal and glaucoma donor eyes, mouse models of glaucoma and mitophagy flux reporter mouse model (mito-qc) as well as transmission electron microscopy (TEM) and the Seahorse assays to determine the role of MAMs, mitophagy and mitochondrial dysfunction in TM function and IOP homeostasis. The successful completion of the proposed studies will provide novel crosstalk between ER stress and mitophagy and target the pathological mechanisms for the treatment of general POAG.
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