Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration

• Published in: International journal of molecular sciences Vol. 24; no. 10; p. 8763
• Main Authors: Lenin, Raji Rajesh, Koh, Yi Hui, Zhang, Zheting, Yeo, Yan Zhuang, Parikh, Bhav Harshad, Seah, Ivan, Wong, Wendy, Su, Xinyi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15-05-2023; MDPI
• Subjects: age-related macular degeneration; Aged; Aging; Apoptosis; Atrophy; Autophagy; Autophagy - genetics; Bioenergetics; Clinical trials; Development and progression; Disease; DNA repair; Drug screening; Free radicals; Gene mutations; Homeopathy; Homeostasis; Humans; Industrialized nations; Light; Lipids; Macular degeneration; Macular Degeneration - pathology; Materia medica and therapeutics; Medical research; Medicine, Experimental; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; mitochondrial dysfunction; Mutation; Nucleic acids; Organelles; Oxidation; Oxidative phosphorylation; Oxidative stress; Oxidative Stress - genetics; Pathogenesis; Phosphorylation; Photoreceptors; Physiological aspects; Proteins; Proteostasis; Retina; retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Review; Therapeutics; Singapore; clinical trials; mitochondrial dysfunction; autophagy; aging; retinal pigment epithelium; age-related macular degeneration
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24108763

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.