Disrupted Mitochondrial and Metabolic Plasticity Underlie Comorbidity between Age-Related and Degenerative Disorders as Parkinson Disease and Type 2 Diabetes Mellitus
Por:
Juárez-Flores DL, Ezquerra M, Gonzàlez-Casacuberta Ï, Ormazabal-Herrero A, Morén C, Tolosa E, Fucho R, Guitart-Mampel M, Casado-Rio M, Valldeoriola F, de la Torre-Lara J, Muñoz E, Tobías E, Compta Y, García-García FJ, García-Ruiz C, Fernandez-Checa JC, Martí MJ, Grau JM, Cardellach F, Artuch-Iriberri R, Fernández-Santiago R and Garrabou G
Publicada:
1 nov 2020
Ahead of Print:
30 oct 2020
Resumen:
Idiopathic Parkinson's disease (iPD) and type 2 diabetes mellitus (T2DM) are chronic, multisystemic, and degenerative diseases associated with aging, with eventual epidemiological co-morbidity and overlap in molecular basis. This study aims to explore if metabolic and mitochondrial alterations underlie the previously reported epidemiologic and clinical co-morbidity from a molecular level. To evaluate the adaptation of iPD to a simulated pre-diabetogenic state, we exposed primary cultured fibroblasts from iPD patients and controls to standard (5 mM) and high (25 mM) glucose concentrations to further characterize metabolic and mitochondrial resilience. iPD fibroblasts showed increased organic and amino acid levels related to mitochondrial metabolism with respect to controls, and these differences were enhanced in high glucose conditions (citric, suberic, and sebacic acids levels increased, as well as alanine, glutamate, aspartate, arginine, and ornithine amino acids; p-values between 0.001 and 0.05). The accumulation of metabolites in iPD fibroblasts was associated with (and probably due to) the concomitant mitochondrial dysfunction observed at enzymatic, oxidative, respiratory, and morphologic level. Metabolic and mitochondrial plasticity of controls was not observed in iPD fibroblasts, which were unable to adapt to different glucose conditions. Impaired metabolism and mitochondrial activity in iPD may limit energy supply for cell survival. Moreover, reduced capacity to adapt to disrupted glucose balance characteristic of T2DM may underlay the co-morbidity between both diseases. Conclusions: Fibroblasts from iPD patients showed mitochondrial impairment, resulting in the accumulation of organic and amino acids related to mitochondrial metabolism, especially when exposed to high glucose. Mitochondrial and metabolic defects down warding cell plasticity to adapt to changing glucose bioavailability may explain the comorbidity between iPD and T2DM.
Filiaciones:
Juárez-Flores DL:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Ezquerra M:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Gonzàlez-Casacuberta Ï:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Ormazabal-Herrero A:
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Department of Clinical Biochemistry, Institut de Recerca de Sant Joan de Deu, Esplugues de Llobregat, 08036 Barcelona, Spain
Morén C:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Tolosa E:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Parkinson Disease and Movement Disorders Unit, Neurology Service, HCB, IDIBAPS, UB, 08036 Barcelona, Spain
Fucho R:
Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), 08001 Barcelona, Spain
Liver Unit-HCB, IDIBAPS, 08036 Barcelona, Spain
Guitart-Mampel M:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Casado-Rio M:
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Department of Clinical Biochemistry, Institut de Recerca de Sant Joan de Deu, Esplugues de Llobregat, 08036 Barcelona, Spain
Valldeoriola F:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Parkinson Disease and Movement Disorders Unit, Neurology Service, HCB, IDIBAPS, UB, 08036 Barcelona, Spain
de la Torre-Lara J:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Muñoz E:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Parkinson Disease and Movement Disorders Unit, Neurology Service, HCB, IDIBAPS, UB, 08036 Barcelona, Spain
Tobías E:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Compta Y:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Parkinson Disease and Movement Disorders Unit, Neurology Service, HCB, IDIBAPS, UB, 08036 Barcelona, Spain
García-García FJ:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
García-Ruiz C:
Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), 08001 Barcelona, Spain
Liver Unit-HCB, IDIBAPS, 08036 Barcelona, Spain
USC Research Centre for ALPD, Keck School of Medicine, Los Angeles, CA 90033, USA
Fernandez-Checa JC:
Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), 08001 Barcelona, Spain
Liver Unit-HCB, IDIBAPS, 08036 Barcelona, Spain
USC Research Centre for ALPD, Keck School of Medicine, Los Angeles, CA 90033, USA
Martí MJ:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Parkinson Disease and Movement Disorders Unit, Neurology Service, HCB, IDIBAPS, UB, 08036 Barcelona, Spain
Grau JM:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Cardellach F:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Artuch-Iriberri R:
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Department of Clinical Biochemistry, Institut de Recerca de Sant Joan de Deu, Esplugues de Llobregat, 08036 Barcelona, Spain
Fernández-Santiago R:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, IDIBAPS, Institut de Neurociències, UB, 08036 Barcelona, Spain
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED CB06/05/0018), 28029 Madrid, Spain
Garrabou G:
Laboratory of Muscle Research and Mitochondrial Function, Department of Internal Medicine-Hospital Clínic of Barcelona (HCB), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science, University of Barcelona (UB), 08036 Barcelona, Spain
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
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