Melatonin protects against common deletion of mitochondrial DNA‐augmented mitochondrial oxidative stress and apoptosis

Abstract

Defected mitochondrial respiratory chain (RC), in addition to causing a severe ATP deficiency, often augments reactive oxygen species (ROS) generation in mitochondria (mROS) which enhances pathological conditions and diseases. Previously, we demonstrated a potent endogenously RC defect-augmented mROS associated dose-dependently with a commonly seen large-scale deletion of 4977 base pairs of mitochondrial DNA (mtDNA), i.e. the common deletion (CD). As current treatments for CD-associated diseases are rather supplementary and ineffective, we investigated whether melatonin, a potential mitochondrial protector, provides beneficial protection for CD-augmented mitochondrial oxidative stress and apoptosis particularly upon the induction of a secondary oxidative stress. Detailed mechanistic investigations were performed by using laser scanning dual fluorescence imaging microscopy to provide precise spatial and temporal resolution of mitochondrial events at single cell level. We demonstrate, for the first time, that melatonin significantly prevents CD-augmented mROS formation under basal conditions as well as at early time-points upon secondary oxidative stress induced by H2O2 exposure. Thus, melatonin prevents mROS-mediated depolarization of mitochondrial membrane potential (DeltaPsim) and subsequent opening of the mitochondrial permeability transition pore (MPTP) and cytochrome c release. Moreover, melatonin prevents depletion of cardiolipin which appears to be crucial for postponing later MPTP opening, disruption of the mitochondrial membrane and apoptosis. Finally, the protection provided by melatonin is superior to those caused by the suppression of mitochondrial Ca2+ regulators including the mitochondrial Na+-Ca2) exchanger, the MPTP, and the mitochondrial Ca2+ uniporter and by antioxidants including vitamin E and mitochondria-targeted coenzyme Q, MitoQ. As RC defect-augmented endogenous mitochondrial oxidative stress is centrally involved in a variety of pathological conditions and diseases, melatonin thus may serve as a therapeutic drug to benefit many clinical conditions that involve malfunction of the mitochondria.

Effects of Melatonin on Nervous System Aging: Neurogenesis and Neurodegeneration

“…In the hippocampus, the reduction of most antioxidant enzymes supports the role of oxidative stress in aging (171). Melatonin and its metabolites have an antioxidant role (172,48). In the CNS, two major metabolites of melatonin, AFMK and AMK, act as free radical scavengers (55).…”

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“…Significant increase of total anti-oxidative status (TAS) level in plasma of multiple sclerosis (MS) patients has been observed with melatonin supplementation 95 . In animal models, melatonin has been demonstrated to prevent the damage to mitochondrial and nuclear DNA by carcinogens [97][98][99][100][101] .…”

Effect of melatonin and/or cysteamine on development and vitrification of buffalo embryos

“…Also, melatonin prevents lipid peroxidation [39]; protein, and DNA [19,40]. In addition, it was found that melatonin preserve the function of mitochondria through reducing and preventing ROS [20], as well as enhancing mitochondrial distribution activity and patterns during nuclear maturation phase [31], and preventing or reducing apoptosis level [21]. Lately, it had been stated that melatonin can ensure its valuable effects through activation of MTNR1A receptorin both granulosa cells and oocyte [31,32], and MTNR1B receptor only in cumulus cells [31,32,41].…”

“…Additionally, melatonin preserves optimal mitochondrial homeostasis and function by reducing and preventing mitochondrial ROS [20], thereby preventing cell death by limiting apoptotic events [21].…”