mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca2+, and lipid insults in NARP cybrids: a potential therapeutic target for melatonin

• Published in: Journal of pineal research Vol. 52; no. 1; pp. 93 - 106
• Main Authors: Peng, Tsung-I, Hsiao, Chia-Wei, Reiter, Russel J., Tanaka, Masashi, Lai, Yiu-Kay, Jou, Mei-Jie
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012
• Subjects: arachidonic acid; Ca2; cardiolipin; fission; melatonin; mitochondrial dynamics; mitochondrial movement; mtDNA T8993G; NARP; reactive oxygen species
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/j.1600-079X.2011.00923.x

:  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, Ca2+, 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 > Ca2+ > lipid), rescues differentially CL‐altered mitochondrial dynamics and cell death (oxidation > Ca2+ > lipid). Thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability transition modulator to antagonize mitochondrial Ca2+ 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.