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

Tsung I. Peng, Chia Wei Hsiao, Russel J. Reiter, Masashi Tanaka, Yiu Kay Lai, Mei Jie Jou

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)93-106
Number of pages14
JournalJournal of pineal research
Volume52
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Ca
  • NARP
  • arachidonic acid
  • cardiolipin
  • fission
  • melatonin
  • mitochondrial dynamics
  • mitochondrial movement
  • mtDNA T8993G
  • reactive oxygen species

ASJC Scopus subject areas

  • Endocrinology

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