The first two authors contributed equally to this work.
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
Article first published online: 4 AUG 2011
© 2011 John Wiley & Sons A/S
Journal of Pineal Research
Volume 52, Issue 1, pages 93–106, January 2012
How to Cite
Peng, T.-I., Hsiao, C.-W., Reiter, R. J., Tanaka, M., Lai, Y.-K. and Jou, M.-J. (2012), 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. Journal of Pineal Research, 52: 93–106. doi: 10.1111/j.1600-079X.2011.00923.x
- Issue published online: 12 DEC 2011
- Article first published online: 4 AUG 2011
- Accepted manuscript online: 30 JUN 2011 04:58AM EST
- Received June 8, 2011; Accepted June 24, 2011.
- arachidonic acid;
- mitochondrial dynamics;
- mitochondrial movement;
- mtDNA T8993G;
- reactive oxygen species
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, 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.