Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders

Abstract

Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

“…The protective mechanisms of melatonin on mitochondria are multiple. These include, but are not limited to, a reduction of mitochondrial oxidative stress [150,151], preservation of the mitochondrial membrane potential [152,153,154], upregulation of the antiapoptotic mitochondrial protein/downregulation of the proapoptotic mitochondrial protein, Bax [137,155,156], increased efficiency of ATP production [59,157], reduced release of cytochrome C into the cytosol and the inhibition of caspase 3 activity [158,159]. …”

New Insights into the Role of Oxidative Stress Mechanisms in the Pathophysiology and Treatment of Multiple Sclerosis

“…It was confirmed that melatonin also plays an important role in improving the antioxidant defense in MS through upregulation of sirtuin 1 (SIRT1) and its target genes for MnSOD and CAT [100]. Moreover, melatonin is selectively taken up by mitochondrial membranes, which makes it a potential therapeutic tool in treating neurodegenerative disorders [50]. …”

The Roles of Melatonin in Parkinson’s Disease: An Overview

“…Subsequently, mitochondria become a site where it is responsible for the overproduction of ROS, therefore the main source of free radicals in cells. The elevation in hydrogen ion-electrochemical gradient is another result obtained from the transferring of metabolic substrates via ETC to molecular oxygen [40]. Evidences of Complex I and glutathione (GSH) deficiencies in substantia nigra are reported in most of the PD patients, hence supported the relationship between PD and mitochondrial dysfunction.…”