The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

Abstract

Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

“…A balance between oxidative species and antioxidant defense mechanisms is required for cell homeostasis [ 130 ]. Briefly, the antioxidant response is mediated by enzymes responsible for metabolizing or neutralizing ROS, such as catalase, glutathione peroxidase, or superoxide dismutase (SODs) [ 131 ].…”

“…The high proportion of ROS generation in MRC is due to the transfer of electrons in the inner mitochondrial membrane until they encounter oxygen, when electrons are converted in water. Under hypoxia or pathologic conditions this process is not completed, resulting in an increase of superoxide anions [ 131 ]. For example, mutation in SOD2, an antioxidant enzyme encoded in the mitochondrial genome, triggers the development of CMT, a NMD [ 132 ].…”

“…This results in an increase of misfolded protein elimination, and escalating the size of the ER compartment thereby reducing the ER stress [ 98 ]. Usually, transient ER stress can be overcome by UPR, but if the damaging stimulus persists, inflammatory response genes are activated [ 131 ].…”

“…Under oxidative stress and in response to inflammation, NLRP3 can be translocated to MAMs. MAMs transmit danger signals through physical interaction, promoting coordinated responses to oxidative stress, such as triggering mitophagy to remove damaged mitochondria [ 131 ].…”

Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa

“…Photoreceptors are particularly sensitive to oxidative damage exerted by the light, with which they constantly interact [ 45 , 46 , 47 ]. In fact, to phototransduce electromagnetic radiation into visual stimuli, retinal cells contain numerous photosensitive molecules, a considerable amount of polyunsaturated fatty acids (15% of photoreceptor’s mass) and are characterized by an extremely high metabolism, from which unstable metabolic byproducts, called ROS, are continuously generated.…”