Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Abstract

Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

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

“…Failure in any of the components of the machinery controlling mitochondrial dynamics may lead to RPE degeneration. Impairment of autophagy/mitophagy leads to increased protein aggregation in RPE and mitochondrial dysfunction evokes chronic RPE-derived inflammation [56].…”

“…In fact, an exquisite balance between mitochondria biogenesis and damaged mitochondrial clearance by either the ubiquitin-proteasome system and lysosomal mitophagy, and between mtDNA replication and repair pathways is crucial for proper RPE function. Any alteration of mitochondrial homeostasis leads to macular damage, a hallmark of AMD degeneration (as recently and comprehensively reviewed [56].…”

Nanoceria Particles Are an Eligible Candidate to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment Epithelium Cell Death and Autophagy Alterations

“…Moreover, RPE cells are essential to provide nutrients to the neuroretina for vitamin A metabolism, for shedding the photoreceptor outer segments (POS), and, therefore, for the visual cycle [4]. Given the fundamental role of the RPE in retinal homeostasis, its dysfunction and cell death are key factors involved in the development of several retinal disorders, including age-related macular degeneration (AMD) [5], which is the leading cause of blindness in advanced age [6,7]. In particular, the dry form of AMD is characterized by progressive lipofuscin/drusen accumulation associated with the slow apoptosis of RPE, neuroretina, and choriocapillaris and, in the end, with permanent central vision loss [8,9].…”

“…The molecular mechanisms underlying the RPE dysfunction and death are not yet fully understood. Among these, autophagy is considered a key mechanism for RPE cells' homeostasis maintenance [18] and may be implicated in AMD development [5,[19][20][21]. The physiological functions of autophagy rely on the removal of damaged organelles and proteins [22].…”

Zinc and Autophagy in Age-Related Macular Degeneration

“…Third, CQ may induce oxidative stress as it decreases the level of glutathione and increases lipid peroxidation [64,107]. All three mechanisms can be linked with AMD pathogenesis [108]. Peters et al observed that CQ-treated rats showed enlargement of the space between the RPE and BM, with the accumulation of residual material from phagosomes [105].…”