Nutraceuticals/Drugs Promoting Mitophagy and Mitochondrial Biogenesis May Combat the Mitochondrial Dysfunction Driving Progression of Dry Age-Related Macular Degeneration

• Published in: Nutrients Vol. 14; no. 9; p. 1985
• Main Authors: Lewis Luján, Lidianys María, McCarty, Mark F, Di Nicolantonio, James J, Gálvez Ruiz, Juan Carlos, Rosas-Burgos, Ema Carina, Plascencia-Jatomea, Maribel, Iloki Assanga, Simon Bernard
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.05.2022; MDPI
• Subjects: age-related macular degeneration; AMP-Activated Protein Kinases - metabolism; AMPK; Apoptosis; Astaxanthin; Autocrine signalling; Berberine; Berberine - pharmacology; Broccoli; Cell death; Dietary Supplements; DNA, Mitochondrial - metabolism; Drugs; Ferulic acid; Functional foods & nutraceuticals; Gene expression; Glucosamine; Humans; Impact damage; Inflammasomes; Inflammasomes - metabolism; Interleukin 18; Kinases; Lipoic acid; Macular degeneration; Macular Degeneration - drug therapy; Melatonin; Melatonin - metabolism; Membrane potential; Metformin; Mitochondria; Mitochondria - metabolism; mitochondrial biogenesis; Mitochondrial DNA; Mitophagy; Molecular biology; mRNA; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; nutraceuticals; Organelle Biogenesis; Oxidants; Oxidation; Oxidative Stress; Oxidizing agents; PPAR alpha - metabolism; Retinal Pigment Epithelium - metabolism; Review; RNA - metabolism; RNA editing; Sirt1; SIRT1 protein; Sirtuin 1 - metabolism; Thioctic Acid; ferulic acid; Nrf2; nutraceuticals; AMPK; Sirt1; melatonin; age-related macular degeneration; mitochondrial biogenesis; astaxanthin; berberine
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu14091985

In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria-inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD. It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin urolithin A and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the: ferulic acid, melatonin, glucosamine, berberine, lipoic acid, and astaxanthin, may have potential for control of dry AMD.