Enhancing Mitochondrial Function in the Context of Age-Related Macular Degeneration
Retinal degeneration is a prevalent issue in later life, and age-related macular degeneration is the poster child for this class of conditions. It is irreversible at present, setting aside a few technology demonstrations of gene therapies and cell therapies, but researchers are seeking cost-effective ways to at least slow it down. Mitochondria are the power plants of the cell, responsible for packaging energy store molecules to power cellular processes. They also generate potentially harmful free radicals while doing so. Mitochondrial function declines with age, less packaging and more free radicals, and this contributes to issues in many tissues, including the retina. A range of present approaches can improve mitochondrial function, such as NAD+ upregulation via vitamin B3 derivatives, or mitochondrially targeted antioxidants, but none of them appear to be any better than exercise. Perhaps the next generation of such technologies will be, but this remains to be seen.
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 PPARĪ± 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 (PPARĪ±). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the above may have potential for control of dry AMD.