Long-term Aβ exposure augments mCa2+-independent mROS-mediated 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.
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 Ca(2+) (mCa(2+))-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 (∆Ψ(m)) and reduce mCa(2+) 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 Aβ-augmented mROS formation and therefore significantly reduced mROS-mediated depolarization of ∆Ψ(m), 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 ∆Ψ(m) and lowered elevated mCa(2+) to sublethal levels for an enhanced mCa(2+)-dependent O(2) consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.
Department of Life Science and Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
Chia-Wei
CW
Hsiao
Tsung-I
TI
Peng
Alexander C
AC
Peng
Russel J
RJ
Reiter
Masashi
M
Tanaka
Yiu-Kay
YK
Lai
Mei-Jie
MJ
Jou
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism*; D006801:Humans; D008550:Melatonin / Q000627:therapeutic use*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D017240:Mitochondrial Myopathies / Q000188:drug therapy; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000188:drug therapy
D016229:Amyloid beta-Peptides; D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D008550:Melatonin; D002118:Calcium
amyloid β‐peptide; cardiolipin; mCa2+; melatonin; mitochondrial reactive oxygen species; neurological muscle weakness, ataxia, and retinitis pigmentosa cybrids; transient‐MPT