Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.

About one-third of individuals with diabetes develop diabetic retinopathy (DR), with one-tenth experiencing vision-threatening conditions such as diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR). Current treatments only show recovery in 50% of cases, and the disease often remains asymptomatic. Therefore, novel early detection methods and new biomarkers are crucial. Our study aims to summarise evidence on the role of altered exosomal regulatory noncoding RNAs in DR, based on human studies. Observational studies delineating the different exosomal noncoding RNAs in DR were searched systematically from inception to June 2024 in PubMed-MEDLINE and SCOPUS databases. Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) 2020 guidelines was used to conduct this systematic review (Prospero ID: CRD42023406724). We synthesised data from 13 human studies that assessed the expression of exosomal regulatory ncRNAs from individuals with DR. Among the 13 studies, nine focused on miRNA, while three examined lncRNA and one on circRNA. Although no common genes were identified across the studies, the review underscores the critical roles of exosomal noncoding RNAs in the pathogenesis of diabetic retinopathy, highlighting their potential as therapeutic targets. Future studies should aim for a unified approach in terms of sample selection, RNA analysis, and appropriate controls for a comprehension of exosomal expression patterns for early diagnosis of DR.

With the recent advances in anti-amyloid therapies, disease-modifying strategies for Alzheimer’s disease (AD) have largely focused on the amyloid cascade hypothesis. However, the optimal therapeutic interventions remains a matter of ongoing debate. It is still unclear whether targeting the amyloid cascade alone is sufficient or if a multitargeted therapeutic approach is obligatory. This question remains particularly important; given that effective long-term disease-modifying therapies for AD continue to be limited. Strong genetic evidence from AD involving mutations in APP, PSEN1, and PSEN2 supports a causal role for the early-onset familial AD. However, most Alzheimer’s cases are sporadic and likely to arise from multifactorial cellular stress pathways that extend beyond amyloid accumulation alone. Increasing evidence suggests that, particularly in sporadic AD, Aβ accumulation may also reflect a downstream consequence of neuronal stress rather than its sole initiating event. Mitochondrial dysfunction, oxidative stress, lysosomal dysfunction, blood-brain barrier (BBB) rupture, microglial transition states and impaired protein clearance are now recognized as early and interconnected cascade of signalling events in AD pathogenesis. In this context, PTEN-induced kinase 1 (PINK1), a central regulator of mitophagy, has gained attention for its role in maintaining mitochondrial and cellular homeostasis. From this viewpoint, we propose the hypothesize that PINK1 could be a direct “amyloid switch” that can be considered as a part of broader cellular resilience cascading signalling event.