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

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 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.

Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini‐infected and N‐nitrosodimethylamine‐treated hamsters

“…Melatonin and its metabolites are well‐known strong antioxidants . Its role has been shown to improve mitochondrial function, mitochondrial homeostasis, reducing mitochondrial oxidative stress , anticancer, and oncostatic actions in a variety of experimental models of neoplasia . The present authors have previously reported that melatonin suppressed inflammation‐mediated DNA damage via balancing the oxidant/antioxidant equilibrium in O. viverrini ‐infected hamsters .…”

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

“…The point is that mitochondrial biogenesis exhibits a strong association with the melatonin circadian rhythm in pinealocytes. In addition to pinealocytes, melatonin was also reported to regulate the mitochondrial fission/fusion in other cell types [186,187]. The mitochondrial fission/fusion machinery is involved in generating young mitochondria, while eliminating old, damaged, and non-repairable ones.…”

“…Fission is generally related to the cellular injury and apoptosis and fusion is associated with healthy cells. Under most conditions, an elevated melatonin concentration results in decreased mitochondrial fission but elevated mitochondrial fusion [138,184,185,186,187,188,189]. Mechanistically, melatonin attenuates the mitochondrial translocation of mitochondrial fission proteins mitochondrial fission 1 protein (Fis1), dynamin-related protein 1 (Drp1) and the pro-apoptotic protein, Bax, as well as upregulating mitochondrial fusion proteins (mitofusins 1 and 2 (Mfn1/2)) and optic atrophy 1 (Opa1).…”

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

“…Prooxidation of the bond between cardiolipin and AAC causes configurational modification of AAC to its open form, i.e., mtPTP opening. Melatonin protects cardiolipin from pro-oxidation and therefore maintains the closed configuration of AAC to inhibit mtPTP opening (113)(114)(115).…”