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This study investigated whether mtDNA<\/jats:styled-content> T8993G<\/jats:styled-content> mutation\u2010induced complex V<\/jats:styled-content> inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP<\/jats:styled-content>), is a potential risk factor for AD<\/jats:styled-content> and the pathological link for long\u2010term exposure of A<\/jats:styled-content>\u03b2\u2010induced mitochondrial toxicity and apoptosis in NARP<\/jats:styled-content> cybrids. Using noninvasive fluorescence probe\u2013coupled laser scanning imaging microscopy and NARP<\/jats:styled-content> cybrids harboring 98% mutant genes along with its parental 143B<\/jats:styled-content> osteosarcoma cells, we demonstrated that A<\/jats:styled-content>\u03b2\u2010augmented mitochondrial C<\/jats:styled-content>a2+<\/jats:sup> (mC<\/jats:styled-content>a2+<\/jats:sup>)\u2010independent mitochondrial reactive oxygen species (mROS<\/jats:styled-content>) formation for a cardiolipin (CL<\/jats:styled-content>, a major mitochondrial protective phospholipid)\u2010dependent lethal modulation of the mitochondrial permeability transition (MPT<\/jats:styled-content>). A<\/jats:styled-content>\u03b2 augmented not only the amount but also the propagation rate of mROS<\/jats:styled-content>\u2010induced mROS<\/jats:styled-content> formation to significantly depolarize mitochondrial membrane potential (\u2206\u03a8m<\/jats:sub>) and reduce mC<\/jats:styled-content>a2+<\/jats:sup> stress. A<\/jats:styled-content>\u03b2\u2010augmented mROS<\/jats:styled-content> oxidized and depleted CL<\/jats:styled-content>, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP<\/jats:styled-content>\u2010augmented lethal transient\u2010MPT<\/jats:styled-content> (t\u2010MPT<\/jats:styled-content>) to switch to its irreversible mode of permanent\u2010MPT<\/jats:styled-content> (p\u2010MPT<\/jats:styled-content>). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced A<\/jats:styled-content>\u03b2\u2010augmented mROS<\/jats:styled-content> formation and therefore significantly reduced mROS<\/jats:styled-content>\u2010mediated depolarization of \u2206\u03a8m<\/jats:sub>, fission of mitochondria and retardation of mitochondrial movement to stabilize CL<\/jats:styled-content> and hence the MPT<\/jats:styled-content>. In the presence of melatonin, A<\/jats:styled-content>\u03b2\u2010promoted p\u2010MPT<\/jats:styled-content> was reversed to a protective t\u2010MPT<\/jats:styled-content>, which preserved \u2206\u03a8m<\/jats:sub> and lowered elevated mC<\/jats:styled-content>a2+<\/jats:sup> to sublethal levels for an enhanced mC<\/jats:styled-content>a2+<\/jats:sup>\u2010dependent O<\/jats:styled-content>2<\/jats:sub> consumption. Thus, melatonin may potentially rescue AD<\/jats:styled-content> patients associated with NARP<\/jats:styled-content> symptoms.<\/jats:p>","DOI":"10.1111\/jpi.12004","type":"journal-article","created":{"date-parts":[[2012,8,2]],"date-time":"2012-08-02T04:15:25Z","timestamp":1343880925000},"page":"107-125","source":"Crossref","is-referenced-by-count":24,"title":["Long\u2010term A<\/scp>\u03b2 exposure augments mC<\/scp>a2+<\/sup>\u2010independent mROS<\/scp>\u2010mediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP<\/scp> cybrids: a protective targeting of melatonin"],"prefix":"10.1111","volume":"54","author":[{"given":"Chia\u2010Wei","family":"Hsiao","sequence":"first","affiliation":[{"name":"Department of Life Science and Institute of Biotechnology National Tsing Hua University Hsinchu Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsung\u2010I.","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurology Kee\u2010Lung Medical Center Chang Gung Memorial Hospital Kee\u2010Lung Taiwan"},{"name":"Department of Medicine Chang Gung University Tao\u2010Yuan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander C.","family":"Peng","sequence":"additional","affiliation":[{"name":"The Williston Northampton School Easthampton MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russel J.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Cellular and Structural Biology Health Science Center University of Texas San Antonio TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Genomics for Longevity and Health Tokyo Metropolitan Institute of 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