Long-term Ab exposure augments mCa2+-independent mROSmediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids: A protective targeting of melatonin

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

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Abstract

Mitochondrial dysfunction is a hallmark of amyloid β-peptide (Aβ)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aβ-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98% mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aβ-augmented mitochondrial Ca2+ (mCa2+)-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aβ augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (ΔΨ m) and reduce mCa2+ stress. Aβ-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Ab-augmented mROS formation and therefore significantly reduced mROSmediated depolarization of ΔΨm, fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aβ-promoted p-MPT was reversed to a protective t-MPT, which preserved ΔΨm and lowered elevated mCa2+ to sublethal levels for an enhanced mCa2+-dependent O2 consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.

Original languageEnglish (US)
Pages (from-to)107-125
Number of pages19
JournalJournal of Pineal Research
Volume54
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Cardiolipins
Retinitis Pigmentosa
Muscle Weakness
Melatonin
Ataxia
Permeability
Reactive Oxygen Species
Alzheimer Disease
Mitochondrial Dynamics
Mitochondrial Membrane Potential
Osteosarcoma
Mitochondrial DNA
Amyloid
Confocal Microscopy
Phospholipids
Mitochondria
Fluorescence
Apoptosis
Mutation
Genes

Keywords

  • Amyloid β-peptide
  • Ataxia and retinitis pigmentosa cybrids
  • Cardiolipin
  • MCa
  • Melatonin
  • Mitochondrial reactive oxygen species
  • Neurological muscle weakness
  • Transient-MPT

ASJC Scopus subject areas

  • Endocrinology

Cite this

Long-term Ab exposure augments mCa2+-independent mROSmediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids : A protective targeting of melatonin. / Hsiao, Chia Wei; Peng, Tsung I.; Peng, Alexander C.; Reiter, Russel J; Tanaka, Masashi; Lai, Yiu Kay; Jou, Mei Jie.

In: Journal of Pineal Research, Vol. 54, No. 1, 01.2013, p. 107-125.

Research output: Contribution to journalArticle

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abstract = "Mitochondrial dysfunction is a hallmark of amyloid β-peptide (Aβ)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aβ-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98{\%} mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aβ-augmented mitochondrial Ca2+ (mCa2+)-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aβ augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (ΔΨ m) and reduce mCa2+ stress. Aβ-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Ab-augmented mROS formation and therefore significantly reduced mROSmediated depolarization of ΔΨm, fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aβ-promoted p-MPT was reversed to a protective t-MPT, which preserved ΔΨm and lowered elevated mCa2+ to sublethal levels for an enhanced mCa2+-dependent O2 consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.",
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AU - Peng, Tsung I.

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AB - Mitochondrial dysfunction is a hallmark of amyloid β-peptide (Aβ)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aβ-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98% mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aβ-augmented mitochondrial Ca2+ (mCa2+)-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aβ augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (ΔΨ m) and reduce mCa2+ stress. Aβ-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Ab-augmented mROS formation and therefore significantly reduced mROSmediated depolarization of ΔΨm, fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aβ-promoted p-MPT was reversed to a protective t-MPT, which preserved ΔΨm and lowered elevated mCa2+ to sublethal levels for an enhanced mCa2+-dependent O2 consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.

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