Protein misfolding and mitochondrial dysfunction in glaucoma

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure caused by restricted outflow of the aqueous humor leads to the degeneration of retinal ganglion cells (RGCs) and their axons. Emerging evidence suggests that pathological mechanisms relating to protein folding and mitochondrial dysfunction are significant factors in the disease onset of different types of open-angle glaucoma. In this review, we discuss these defects in three distinct types of open-angle glaucoma: primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and exfoliation glaucoma (XFG). Genetic mutations linked to the previously mentioned open-angle glaucoma, including those in myocilin (MYOC), optineurin (OPTN), and lysyl oxidase 1 (LOXL1), disrupt protein folding and homeostasis, leading to endoplasmic reticulum stress, activation of the unfolded protein response and impaired autophagic protein degradation. These factors contribute to trabecular meshwork and retinal ganglion cell apoptosis. In addition to protein folding defects, mitochondrial dysfunction is also associated with the progression of trabecular meshwork damage and the death of RGCs. Factors such as oxidative stress, an altered mitochondrial fission-fusion balance, and mitophagy dysregulation make RGCs vulnerable and contribute to optic nerve degeneration. The crosstalk between protein folding and mitochondrial defects in glaucoma underscores the complexity of disease pathogenesis and offers potential targets for therapeutic intervention. Strategies aimed at restoring protein homeostasis, enhancing mitochondrial function, and mitigating cellular stress responses hold promise for neuroprotection in glaucoma.

Keywords: NTG; POAG; XFG; autophagy; er stress; glaucoma; mitochondrial dysfunction; upr.

FIGURE 1

ER protein quality control mechanisms (A) Protein folding in ER lumen. Newly synthesized proteins that are translocated to the ER by the SEC61 translocon are folded by various ER chaperones. While the CRT/CNX cycle aids glycoproteins, PDI oxidizes cysteine residues to promote disulfide bond formation. Properly folded proteins can exit the organelle in vesicles. (B) ER stress and UPR activation. BIP removes its interaction from the three UPR signaling pathways in response to ER stress, initiating adaptive signaling. The PERK, IRE1α, and ATF6 pathways parallelly activate downstream modulators and regulate the gene expression to restore ER homeostasis. However, prolonged ER stress leads to the activation of cellular apoptosis. (C) ERAD degradation of substrate proteins. The ERAD substrates recognized by the chaperones are ubiquitinated and retro-translocated to the cytoplasm by the SEL1-HRD1 complex. In the cytoplasm, the CDC48/P97/VCP ATPase trims and re-ubiquitinates the substrates before being handed over to the proteasome for degradation. (D) ER-phagy mechanism. One of the ER-phagy receptors, FAM134B, identifies the ER subdomain that contains protein aggregates, aided by the chaperone CNX, for selective degradation. The receptor’s oligomerization at the ER sheets’ edge induces curvature in the ER membrane. Further, the interaction between the ER-phagy receptor and LC3/GABARAP facilitates the sequestration of ER regions within autophagosomes.

FIGURE 2

Defects in protein folding and proteostasis in glaucoma (A) MYOC variants causing POAG. MYOC mutations lead to amyloid-like protein aggregation, while insufficient secretion results in ER stress and activates the PERK-ATF4-CHOP UPR pathway. Further, the inadequate ERAD and defects in autophagic flux cause TM and RGC cell death through apoptosis, which leads to IOP elevation and glaucomatous neurodegeneration. (B) OPTN variants causing NTG. OPTN mutations cause altered localization with increased foci formation around the Golgi apparatus. The enhanced interaction of E50K OPTN with TBK1 affects RAB8-mediated vesicular trafficking and autophagosome formation, which ultimately contributes to RGC apoptosis and glaucomatous neurodegeneration. (C) LOXL1 polymorphisms contribute to the risk of XFG. In XFG, the exfoliative fibrillar aggregate material builds up because of the loss of cellular proteostasis, resulting in ER stress, UPR, defective ERAD, and autophagy. The pathogenic LOXL1 variant expression also caused aggregation, ER-oxidative stress, and defective autophagy.

FIGURE 3

Mitochondrial dynamics, biogenesis, respiration, and mitophagy (A) Mitochondrial fission and fusion mechanisms. Mitochondria continuously undergo fission and fusion cycles. DRP1 regulates the fission process, while MFN1 and OPA1 drive its fusion. (B) Mitochondrial biogenesis and respiration. Involvement of, ETC, in ATP production. ER releases Ca²⁺ through the IP3R receptor, which is imported into the mitochondrial matrix via MCU and released through PTP. (C) PINK1/PARKIN mediated mitophagy pathway. In dysfunctional mitochondria, stabilizing PINK1 in the OMM leads to the activation and recruitment of PARKIN. This action initiates the polyubiquitination of OMM proteins, recruitment of LC3-coated autophagosomes, and degradation of mitochondria in autolysosomes.

FIGURE 4

Mitochondrial dysfunction in glaucoma causes RGC death. In glaucomatous animal models, elevated IOP and oxidative stress result in mtDNA mutations, decreased ATP production, increased fission, enhanced mitochondrial Ca²⁺ transport from the ER, and reduced mitophagy flux, all contributing to RGC cell death.