Abstract
Mitochondria play a central role in the cell physiology. It is now recognized that, besides their classic function of energy metabolism, mitochondria are enrolled in multiple cell functions including energy distribution through the cell, energy/heat modulation, reactive oxygen species (ROS) regulation, calcium homeostasis, and apoptosis control. Recently, evidence is accumulating for a direct participation of mitochondria in stem cell proliferation and/or differentiation. All these functions suggest that mutations in either nuclear or mitochondrial DNA may induce serious cell impairments, and there is now evidence of more than 200 mtDNA mutations responsible for human pathologies. Moreover, mitochondria are, simultaneously, the main producer and target of ROS and, thus, multiple mitochondrial diseases are related to ROSinduced mitochondrial injuries. Among these, neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), inflammatory diseases such as sepsis, and aging itself, are caused or accompanied by ROS-induced mitochondrial dysfunctions. With regard to its action spectrum as an antioxidant, melatonin may be regarded as a firstchoice agent for preventing and/or reducing the excess of ROS, thereby maintaining mitochondrial homeostasis. Multiple in vitro and in vivo experiments have shown the protective role of melatonin on mitochondrial physiology, yielding a significant improvement in those diseases in which energy supply to the cell had been compromised. New lines of evidence suggest the participation of mitochondria in stem cell proliferation and differentiation, and preliminary data support the role of melatonin in these processes. This review accounts for the multiple functions of mitochondria and the mechanisms involved in the numerous beneficial effects of melatonin to maintain mitochondrial homeostasis.
Highlights
Mitochondria are organelles found almost ubiquitously in eukaryotes
Under conditions of oxidative stress, the mitochondrial levels of GSH and reduced pyridine nucleotides are connected through energylinked transhydrogenase and glutathione reductase (GRd) and it is difficult for these compound to independently modulate the S- and the P-site in vivo [21]
The administration of pharmacological doses of melatonin in rodents with sepsis induced by lipopolysacharide injection or cecal ligation and puncture (CLP) produced a decrease in the expression and activity of inducible nitric oxide synthase (iNOS), and nitrite levels, nitrosative/oxidative stress and mitochondrial function were normalized in muscle tissues and liver [51,52,53,54, 149, 160]
Summary
Mitochondria are organelles found almost ubiquitously in eukaryotes. Their small size contradicts their fundamental magnitude to the life and metabolic economy of the cell, as they are the location of a number of vitally important metabolic pathways including Krebs cycle, fatty acid oxidation, and lipid and cholesterol synthesis. All thirteen polypeptides are subunits of the respiratory chain/oxidative phosphorylation system: seven belong to Complex I (C-I) or NADHCoQ oxidoreductase), one to Complex III (C-III) or CoQcytochrome c oxidoreductase, three to Complex IV (C-IV) or cytochrome c oxidase (COX) and two to Complex V (C-V) or ATP synthase These subunits are synthesized within the mitochondrion, where they assemble with a larger number of subunits encoded by nuclear DNA (nDNA) that are synthesized in the cytoplasm and are transported into mitochondrion [3]. While UCP1 is known to play an important role in regulating heat production during cold exposure in some mammals including human babies, possible roles for other UCPs are still controversial and they may include the control of ROS production by mitochondria [10, 11] These UCPs probably do not transport protons except in the presence of specific activators [12]. Under conditions of oxidative stress, the mitochondrial levels of GSH and reduced pyridine nucleotides are connected through energylinked transhydrogenase and glutathione reductase (GRd) and it is difficult for these compound to independently modulate the S- and the P-site in vivo [21]
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