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Property "Has-20abstract" (as page type) with input value "Accumulation-20of-202-2Dmethylcitric-20acid-20(2MCA)-20is-20observed-20in-20methylmalonic-20and-20propionic-20acidemias,-20which-20are-20clinically-20characterized-20by-20severe-20neurological-20symptoms.-20The-20exact-20pathogenetic-20mechanisms-20of-20brain-20abnormalities-20in-20these-20diseases-20are-20poorly-20established-20and-20very-20little-20has-20been-20reported-20on-20the-20role-20of-202MCA.-20In-20the-20present-20work-20we-20found-20that-202MCA-20markedly-20inhibited-20ADP-2Dstimulated-20and-20uncoupled-20respiration-20in-20mitochondria-20supported-20by-20glutamate,-20with-20a-20less-20significant-20inhibition-20in-20pyruvate-20plus-20malate-2Drespiring-20mitochondria.-20However,-20no-20alterations-20occurred-20when-20α-2Dketoglutarate-20or-20succinate-20was-20used-20as-20respiratory-20substrates,-20suggesting-20a-20defect-20on-20glutamate-20oxidative-20metabolism.-20It-20was-20also-20observed-20that-202MCA-20decreased-20ATP-20formation-20in-20glutamate-20plus-20malate-20or-20pyruvate-20plus-20malate-2Dsupported-20mitochondria.-20Furthermore,-202MCA-20inhibited-20glutamate-20dehydrogenase-20(GDH)-20activity-20at-20concentrations-20as-20low-20as-200.5-20mM.-20Kinetic-20studies-20revealed-20that-20this-20inhibitory-20effect-20was-20competitive-20in-20relation-20to-20glutamate.-20In-20contrast,-20assays-20of-20osmotic-20swelling-20in-20non-2Drespiring-20mitochondria-20suggested-20that-202MCA-20did-20not-20significantly-20impair-20mitochondrial-20glutamate-20transport.-20Finally,-202MCA-20provoked-20a-20significant-20decrease-20of-20mitochondrial-20membrane-20potential-20and-20induced-20swelling-20in-20Ca-3Csup-3E2+-3C-2Fsup-3E-20-2Dloaded-20mitochondria-20supported-20by-20different-20substrates.-20These-20effects-20were-20totally-20prevented-20by-20cyclosporine-20A-20plus-20ADP-20or-20ruthenium-20red,-20indicating-20induction-20of-20mitochondrial-20permeability-20transition-20(PT).-20Taken-20together,-20our-20data-20strongly-20indicate-20that-202MCA-20behaves-20as-20a-20potent-20inhibitor-20of-20glutamate-20oxidation-20by-20inhibiting-20GDH-20activity-20and-20as-20a-20PT-20inducer,-20disturbing-20mitochondrial-20energy-20homeostasis.-20We-20presume-20that-202MCA-2Dinduced-20mitochondrial-20deleterious-20effects-20may-20contribute-20to-20the-20pathogenesis-20of-20brain-20damage-20in-20patients-20affected-20by-20methylmalonic-20and-20propionic-20acidemias.-20This-20article-20is-20protected-20by-20copyright.-20All-20rights-20reserved." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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