Autophagy and mechanotransduction in outflow pathway cells

Abstract

Because of elevations in IOP and other forces, cells in the trabecular meshwork (TM) are constantly subjected to mechanical strain. In order to preserve cellular function and regain homeostasis, cells must sense and adapt to these morphological changes. We and others have already shown that mechanical stress can trigger a broad range of responses in TM cells; however, very little is known about the strategies that TM cells use to respond to this stress, so they can adapt and survive. Autophagy, a lysosomal degradation pathway, has emerged as an important cellular homeostatic mechanism promoting cell survival and adaptation to a number of cytotoxic stresses. Our laboratory has reported the activation of autophagy in TM cells in response to static biaxial strain and high pressure. Moreover, our newest data also suggest the activation of chaperon-assisted selective autophagy, a recently identified tension-induced autophagy essential for mechanotransduction, in TM cells under cyclic mechanical stress. In this review manuscript we will discuss autophagy as part of an integrated response triggered in TM cells in response to strain, exerting a dual role in repair and mechanotransduction, and the potential effects of dysregulated in outflow pathway pathophysiology.

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

“…Strain causes profound changes to cell morphology, affecting motility, stiffness, contraction, orientation, and cell alignment (14-16). Recent studies have indicated autophagy as one of the relevant stress response adaptive mechanisms (16, 18, 19). Other genes that are impacted by the mechanical strain include those involved in extracellular matrix synthesis/remodeling, cytoskeletal organization, and cell adhesion (16, 20-25).…”

The Role of Autophagy in Glaucomatous Optic Neuropathy

“…Autophagy is also activated in TM cells exposed to biaxial mechanical stretch and high pressure in a mTOR and BAG3 independent manner; interestingly, cyclic, but not static, mechanical stimulation of TM cells seems to activate a chaperone-assisted selective autophagy (CASA) (Hirt and Liton, 2017), a selective tension-induced autophagy previously described in muscle (Ulbricht et al, 2013).…”

Major review: Molecular genetics of primary open-angle glaucoma

“…Multiple genetic and molecular studies indicate the important contribution of autophagy to the pathogenesis of POAG (Frost et al, 2014; Hirt and Liton, 2017; Liton, 2016; Minegishi et al, 2016; Porter et al, 2015; Porter et al, 2013; Porter et al, 2014; Slowicka et al, 2016; Tucker et al, 2014; Wong and Holzbaur, 2014). As discussed earlier, a number of genetic factors are involved in or associated with the pathogenesis of POAG.…”