August 29, 2023
Until recently, melatonin has been thought of primarily as the “sleep hormone.” The long held belief in scientific research has been that our pineal glands, in response to the light/dark cycle, produced the majority of the melatonin in our bodies. However, new research has shown that the bulk of the melatonin produced in mammals is from the mitochondria of every cell, where its synthesis occurs 24 hours a day and is not impacted by the light/dark cycle.1 This important new discovery shines a light on many more facets of melatonin that have primarily gone under the radar until recently.
What Is Melatonin?
Melatonin is an endogenous indoleamine, or monoamine neurotransmitter, that is synthesized not only in the pineal gland (endocrine gland located in the cranial fossa in charge of producing hormones crucial in the modulation of sleep patterns) but also in each individual cell, specifically at the mitochondrial level.2,3 Independent of its production site, melatonin levels usually vary depending on factors such as aging. Like vitamin D, melatonin has a role in a vast amount of our physiology and impacts cellular processes such as inflammation and oxidative stress, which play a role in every age-related disease of the eye.
Melatonin’s Role in Retinal Health
The retina is highly predisposed to oxidative stress due to intense blood flow, high metabolic rate, the presence of mitochondria-rich cells, high concentrations of easily oxidized polyunsaturated fatty acids in membranes, and prolonged exposure to light. Since reactive oxygen species (ROS) are primarily produced by the respiratory chain of the mitochondria, mitochondria are major sites of oxidative stress. It is important to note that the retina has more mitochondria than any other tissue and ages rapidly.4 Ocular mitochondria are the source of antioxidant and protein repair systems but are also, as stated above, the main endogenous source of ROS. Oxidatively damaged mitochondria are unable to maintain redox balance and to repair damaged proteins. Furthermore, ROS produced by injured mitochondria induce the autophagy/mitophagy process. In the eye, autophagy plays a critical role in maintaining normal cellular function, and alterations in the autophagy process contribute to age-related ocular disease. Melatonin supports the mitochondria of every cell to help maintain homeostasis.
Melatonin as Mitochondrial Support
1. Antioxidant Protection: Melatonin and its metabolites are potent scavengers of reactive ROS and reactive nitrogen species, neutralizing them and preventing oxidative damage to mitochondrial components.5 Melatonin reduces mitochondrial superoxide production and protects mitochondrial DNA from oxidative damage.6
2. Improvement of Respiratory Chain Efficiency: Melatonin enhances the function of Complex IV of the electron transport chain, thereby improving ATP synthesis efficiency and minimizing ROS production.7 This supports energy production while reducing potential oxidative stress.
3. Regulation of Mitochondrial Dynamics: Melatonin can influence mitochondrial biogenesis, fission, and fusion, processes that are essential for maintaining mitochondrial integrity and function.8 By regulating the expression of key proteins such as Mfn2 and Drp1, melatonin maintains the balance between mitochondrial fusion and fission.9
4. Protection Against Mitochondrial Membrane Damage: Melatonin prevents lipid peroxidation in the inner mitochondrial membrane and maintains mitochondrial membrane potential.10 By preserving membrane integrity, melatonin ensures that the mitochondria continue to function effectively.
5. Inhibition of Apoptosis: Melatonin’s anti-apoptotic effects are well documented. Melatonin inhibits cytochrome c release from the mitochondria, preventing activation of the intrinsic apoptosis pathway.11 This can be vital in pathological conditions where mitochondrial dysfunction leads to cell death.
Melatonin’s Potential in Mitigating Eye Disease
Melatonin’s critical role in mitigating oxidative stress and supporting mitochondrial function influences the onset as well as the progression of age-related retinal pathologies, including glaucoma, macular degeneration, and diabetic retinopathy.12 See the summary below of melatonin’s potential in mitigating eye disease:
Cataracts: Mitochondria are abundant in the lens. Aged lens cells are high in ROS and damaged mitochondria and are characterized by lower levels of glutathione.12 Glutathione and mitochondria antioxidant enzymes control redox balance in the lens. Autophagy and mitophagy processes attempt to restore lens homeostasis, but their failings often result in more ROS, oxidation, and finally cataract formation.12, 13 Melatonin counteracts the negative effects of mitochondrial dysfunction that occurs with aging and helps restore lens homeostasis.
Glaucoma: Mitochondrial stress and nitro-oxidative stress are essential in the onset and progression of primary open-angle glaucoma (POAG).12 It has been demonstrated that melatonin can counteract several pathogenic mechanisms for glaucomatous neurodegeneration, including elevated IOP, nitro-oxidative stress, excitotoxicity, and glial activation.12 Exogenous melatonin and its analogues lower IOP in mammals, including humans.12 Melatonin increases retinal antioxidant defenses and reduces lipid peroxidation, NOS activity, the loss of retinal ganglion cells, and the extracellular glutamate level in a model of chronic pressure-induced glaucoma.12 Melatonin has been shown to inhibit glial reactivity and reduce the expression of hypoxia inducible factor 1a, COX-2, and TNFa genes in experimental models of optic neuritis and retinal ischemia.12
Macular Degeneration: Aged photoreceptors, choriocapillaris, and RPE cells are subjected to intense oxidative insult because of their constant exposure to visible light, daily phagocytosis of photoreceptor outer segments, high local oxygen concentrations, presence of intracellular photosensitizers, and choroidal blood photoactive compounds.12, 14 Additionally, RPE cells present inadequate systems of antioxidant defense and mitochondrial DNA repair.12 Melatonin counteracts oxidative stress and increases the viability of RPE cells and photoreceptors.12, 14 Nocturnal melatonin secretion protects photoreceptors against light-induced damage.12, 14 Melatonin induces melanosome aggregation in RPE cells and thereby protects them from light-induced damage.12, 14 Melatonin also protects against the breakdown of the retinal-blood-brain barrier.12 Levels of melatonin decrease with age, and this reduction of melatonin makes cells more vulnerable to all age-related diseases.
Diabetic Retinopathy: Oxidative stress underlies the pathogenesis of diabetic retinopathy.12, 15 Inflammatory processes also contribute to development of diabetic retinopathy, and thus it is considered a low-grade inflammatory disease.12, 16 Melatonin protects from oxidative stress and increases the viability of retinal cells including RPE cells, photoreceptors, retinal ganglion cells, and Müller cells.12 Melatonin prevents nitro-oxidative stress and vascular changes of the diabetic retina.12 Melatonin also helps avoid the high glucose-induced inflammatory response of RPE cells as well as retinal endothelial cells.12
Dry Eye: Dry eye is an inflammatory disease. Recent studies have shown that melatonin has the ability to improve dry eye disease by protecting corneal epithelial cell viability and inhibiting apoptosis from oxidative damage.17 In a recently published study in Experimental Eye Research, mice were injected with scopolamine three times a day and were exposed to a dry environment with humidity less than 30% for seven consecutive days. In addition, primary corneal epithelial cells were exposed to oxidation via hydrogen peroxide.17 The investigators found melatonin significantly protected cell viability and decreased apoptosis in the human corneal epithelial cells exposed to hydrogen peroxide, and the intraperitoneal injection of melatonin in the dry eye mouse model also showed significant improvements. Melatonin was able to reduce ROS production and maintain mitochondrial function, inhibiting inflammation activation.17
Age-related diseases share underlying molecular processes. Oxidative damage, mainly at the mitochondrial level, connects all ocular diseases of aging. Impaired autophagy and low-grade chronic inflammation are also common denominators of age-related ocular diseases. Melatonin’s actions are pleiotropic, including antioxidant/antinitridergic, mitochondrial protection, autophagy modulation, anti-inflammatory, and anti-angiogenic actions in ocular tissues.12 Exogenously supplied melatonin has been proposed as a multitasking molecule capable of acting as an upstream intervention that addresses the core underlying molecular processes that contribute to “inflammaging” and cellular senescence.2
Melatonin is generally considered safe at daily doses of 0.5 to 10 mg. per day. Patients should be advised not to drive or operate machinery for four to five hours after taking melatonin. Every patient is different, and recommendations should be made on a case-by-case basis after a full review of systems and consideration of any prescription or over-the-counter medications that the patient is already taking. Foods high in melatonin include tart cherries, goji berries, eggs, milk, fish, and nuts such as pistachios and almonds.
References
1 Suofu Y, Li W, Jean-Alphonse F, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. 2017. Proc Natl Acad Sci USA 114, e7997-e8006.
2 Martin Gimenez VM, delas Heras N, Lahera V et al. Melatonin as an anti-aging therapy for age-related cardiovascular and neurodegenerative diseases. Frontiers in Aging Neuroscience June 2022, volume 14, article 888292.
3 Yanar K, Simsek B, Cakatay U. 2019. Integration of melatonin related redox homeostasis, aging, and circadian rhythm. Rejuvenation Res 22, 409-419.
4 HohKam J, Shinhmar H, Powner MB, et al. Mitochondrial decline in the ageing old world primate retina: little evidence for difference between the centre and periphery. PLos One. 2023; 18(5).
5 Reiter R, Tan D, Terron M et al. Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochimica Polonica 54 (1), 1-9, 2007.
6 Tan D, Manchester L, Liu W et al. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. Journal of Pineal Research, volume 54, Issue 2, 127-138.
7 Martin M, Macias M, Escames G et al. Melatonin-induced increased activity of the respiratory complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J Pineal Res. 2000 May; 28(4):242-8.
8 Paradies G, Paradies V, Ruggiero F et al. Role of cardiolipin in mitochondrial function and dynamics in health and disease: molecular and pharmacological aspects. Cells. 2019 Jul; 8(7):728.
9 Suofu Y, Li W, Jean-Alphonse F, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci USA. 2017 Sep 19;114(38)E7997-E8006.
10 Jou M, Peng T, Yu P et al. Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis. J Pineal Res. 2007 Nov;43(4):389-403.
11 Andrabi S, Sayeed I, Siemen D et al. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 2004 May;18(7):869-71.
12 Crooke A, Huete-Toral F, Colligris B et al. The role and therapeutic potential of melatonin in age-related ocular diseases. J Pineal Res. 2017;63:e12430.
13 Costello M, Brennan L, Basu S et al. Autophagy and mitophagy participate in ocular lens organelle degradation. Exp Eye Res. 2013;116:141-150.
14 Blasiak J, Reiter R, Kaarniranta k. Melatonin in retinal physiology and pathology: the case of age-related macular degeneration. Oxidative Medicine and Cellular Longevity, volume 2016, article ID 6819736.
15 Gurler B, Vural H, Yilmaz N et al. The role of oxidative stress in diabetic retinopathy. Eye (Lond). 2000;14:730-735.
16 Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2007;2007:95103.
17 Wang B, Zuo X, Peng L et al. Melatonin ameliorates oxidative stress-mediated injuries through induction of HO-1 and restores autophagic flux in dry eye. Experimental Eye Research, April 2021, volume 205, 108491.
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