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- W2980933070 abstract "Mitochondria play a key role in neuronal survival by regulating both energy metabolism and cell death. The mitochondrial permeability transition (mPT) is the main excitotoxic neuronal death pathway during Alzheimer's disease and other neurodegenerative disorders. The opening of the mitochondrial permeability transition pore (mPTP) leads to mitochondrial inner membrane permeabilization and dissipation of membrane potential, followed rapidly by cell death. Despite its vital importance, the exact structural components and mechanisms inducing mPTP opening is poorly understood on the molecular level. Mitochondrial ATP synthase has been shown to play a crucial role in mPT but the oligomeric state of ATP synthase required for channel formation is still being debated. Now, we purified and reconstituted monomeric ATP synthase from porcine heart mitochondria into small unilamellar lipid vesicles (SUVs) and analyzed its oligomeric state by single-particle electron cryomicroscopy. Here, we present the cryo-EM structure of functionally active monomeric ATP synthase in SUVs at ∼16 Å resolution. The patch-clamp recordings reveal that this preparation of SUV-reconstituted ATP synthase monomers, when fused into giant unilamellar vesicles (GUVs), form voltage-gated and Ca2+-activated channels with the key features of mPTP. Based on our findings we conclude that the ATP synthase monomer is sufficient, and dimer formation is not required for its megachannel activity. In-depth structural analysis of ATP synthase will reveal its “open channel” conformation and will lead to a structure-based drug design of specific therapeutic compounds for the treatment of Alzheimer's disease and other neurological disorders." @default.
- W2980933070 created "2019-10-25" @default.
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- W2980933070 date "2019-07-01" @default.
- W2980933070 modified "2023-09-28" @default.
- W2980933070 title "P4-512: EXCITOTOXIC NEURONAL DEATH INDUCING MEGACHANNEL RESIDES IN MONOMERIC F1 FO ATP SYNTHASE" @default.
- W2980933070 doi "https://doi.org/10.1016/j.jalz.2019.08.058" @default.
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