title: mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca(2+), and lipid insults in NARP cybrids: a potential therapeutic target for melatonin.
abstract: Mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. This study investigated how mtDNA T8993G (NARP)-induced inhibition of mitochondrial complex V altered mitochondrial dynamics in association with a protective mitochondrial phospholipid, cardiolipin (CL), as a potential therapeutic target. NARP cybrids harboring 98% of mtDNA T8993G genes and its parental osteosarcoma 143B cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. We demonstrate for the first time that NARP mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxidative, Ca(2+), and lipid stress. In addition, NARP significantly augmented pathological depletion of CL. NARP-augmented depletion of CL results in enhanced retardation of mitochondrial movement and fission and later swelling of mitochondria during all insults. These results suggest that CL is a common and crucial pathological target for mitochondrial apoptotic insults. Furthermore, CL possibly plays a central role in regulating mitochondrial dynamics that are associated with NARP-augmented mitochondrial pathologies. Intriguingly, melatonin, by differentially preserving CL during various stresses (oxidation > Ca(2+) > lipid), rescues differentially CL-altered mitochondrial dynamics and cell death (oxidation > Ca(2+) > lipid). Thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability transition modulator to antagonize mitochondrial Ca(2+) stress, may stabilize directly CL to prevent its oxidization and/or depletion and, therefore, exerts great potential in rescuing CL-dependent mitochondrial dynamics-associated mitochondrial pathologies for treatment of NARP-induced pathologies and diseases.
authors.affiliation: Department of Neurology, Kee-Lung Medical Center, Chang Gung Memorial Hospital, Kee-Lung, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Peng
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Hsiao
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yiu-Kay
authors.initials: YK
authors.lastname: Lai
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
mesh_terms: D000704:Analysis of Variance; D016718:Arachidonic Acid / Q000494:pharmacology; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D005818:Genetic Engineering; D005821:Genetic Techniques; D006801:Humans; D008550:Melatonin / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D016718:Arachidonic Acid; D002097:C-Reactive Protein; D002308:Cardiolipins; D004272:DNA, Mitochondrial; D008550:Melatonin; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D000099153:Pentraxins