Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 May 9;14(9):1985.
doi: 10.3390/nu14091985.

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

Lidianys María Lewis Luján  1 , Mark F McCarty  2 , James J Di Nicolantonio  3 , Juan Carlos Gálvez Ruiz  4 , Ema Carina Rosas-Burgos  1 , Maribel Plascencia-Jatomea  1 , Simon Bernard Iloki Assanga  4
Affiliations
Review

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

Lidianys María Lewis Luján et al. Nutrients. .

Abstract

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.

Keywords: AMPK; Nrf2; Sirt1; age-related macular degeneration; astaxanthin; berberine; ferulic acid; melatonin; mitochondrial biogenesis; nutraceuticals.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A simplified depiction of how DICER1 deficiency in RPE cells leads to Alu RNA excess, mitochondrial damage, NLRP3 inflammasome activation, autocrine IL-18 activity, and caspase-8-mediated cell death.
Figure 2
Figure 2
Roles for Sirt1, AMPK, Nrf2, and PPARα in promotion of mitochondrial biogenesis (MB) and autophagy/mitophagy. FA = ferulic acid; MLT = melatonin; GCA = glucosamine.
See this image and copyright information in PMC

References

    1. Kaneko H., Dridi S., Tarallo V., Gelfand B.D., Fowler B.J., Cho W.G., Kleinman M.E., Ponicsan S.L., Hauswirth W.W., Chiodo V.A., et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature. 2011;471:325–330. doi: 10.1038/nature09830. - DOI - PMC - PubMed
    1. Tarallo V., Hirano Y., Gelfand B.D., Dridi S., Kerur N., Kim Y., Cho W.G., Kaneko H., Fowler B.J., Bogdanovich S., et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell. 2012;149:847–859. doi: 10.1016/j.cell.2012.03.036. - DOI - PMC - PubMed
    1. Kerur N., Hirano Y., Tarallo V., Fowler B.J., Bastos-Carvalho A., Yasuma T., Yasuma R., Kim Y., Hinton D.R., Kirschning C.J., et al. TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Investig. Ophthalmol. Vis. Sci. 2013;54:7395–7401. doi: 10.1167/iovs.13-12500. - DOI - PMC - PubMed
    1. Kim Y., Tarallo V., Kerur N., Yasuma T., Gelfand B.D., Bastos-Carvalho A., Hirano Y., Yasuma R., Mizutani T., Fowler B.J., et al. DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc. Natl. Acad. Sci. USA. 2014;111:16082–16087. doi: 10.1073/pnas.1403814111. - DOI - PMC - PubMed
    1. Mao X., Fang W., Liu Q. An emerging role of Alu RNA in geographic atrophy pathogenesis: The implication for novel therapeutic strategies. Discov. Med. 2016;22:337–349. - PubMed

MeSH terms