title: Mild mitochondrial metabolic deficits by α-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease.
abstract: Brain activities of the mitochondrial enzyme α-ketoglutarate dehydrogenase complex (KGDHC) are reduced in Alzheimer's disease and other age-related neurodegenerative disorders. The goal of the present study was to test the consequences of mild impairment of KGDHC on the structure, protein signaling and dynamics (mitophagy, fusion, fission, biogenesis) of the mitochondria. Inhibition of KGDHC reduced its in situ activity by 23-53% in human neuroblastoma SH-SY5Y cells, but neither altered the mitochondrial membrane potential nor the ATP levels at any tested time-points. The attenuated KGDHC activity increased translocation of dynamin-related protein-1 (Drp1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) from the cytosol to the mitochondria, and promoted mitochondrial cytochrome c release. Inhibition of KGDHC also increased the negative surface charges (anionic phospholipids as assessed by Annexin V binding) on the mitochondria. Morphological assessments of the mitochondria revealed increased fission and mitophagy. Taken together, our results suggest the existence of the regulation of the mitochondrial dynamism including fission and fusion by the mitochondrial KGDHC activity via the involvement of the cytosolic and mitochondrial protein signaling molecules. A better understanding of the link among mild impairment of metabolism, induction of mitophagy/autophagy and altered protein signaling will help to identify new mechanisms of neurodegeneration and reveal potential new therapeutic approaches.
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Kalpita
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: Department of Cellular and Molecular Pharmacology and Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Soumyabrata
authors.initials: S
authors.lastname: Munshi
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Frank
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Huan-Lian
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Department of Pathology and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Yang
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210, USA.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Denton
authors.affiliation: Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Jian Fei
authors.initials: JF
authors.lastname: Jiang
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA. Electronic address: ggibson@med.cornell.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D063065:Organophosphonates / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013386:Succinates / Q000494:pharmacology
chemical_list: D063065:Organophosphonates; D013386:Succinates; C099145:succinyl phosphonate; D007655:Ketoglutarate Dehydrogenase Complex
keywords: Autophagy; Fission; Glucose metabolism; Mitochondria; Mitophagy; Neurodegeneration