title: 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.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, College of Medicine, Chang Gung University, Tao-Yuan, and Department of Neurology, Kee-Lung Medical Center, Chang Gung Memorial Hospital, Taiwan. mjjou@mail.cgu.edu.tw
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Peng
authors.forename: Pai-Zu
authors.initials: PZ
authors.lastname: Yu
authors.forename: Shuo-Bin
authors.initials: SB
authors.lastname: Jou
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Chen
authors.forename: Hong-Yueh
authors.initials: HY
authors.lastname: Wu
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Chen
authors.forename: Lee-Fen
authors.initials: LF
authors.lastname: Hsu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002308:Cardiolipins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics*; D004579:Electron Transport / Q000187:drug effects; D006822:Hybrid Cells; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D002308:Cardiolipins; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D008550:Melatonin