Abstract
Neurodegenerative diseases are accompanied by reduced activity of mitochondrial α-ketoglutarate dehydrogenase multienzyme complex (KGDHC). We present a new cellular model to study molecular mechanisms of this association. By application of the highly specific and efficient inhibitor of KGDHC, succinyl phosphonate (SP), to cultured neurons, we characterized the concentrationand time-dependent consequences of decreased KGDHC activity for neuronal metabolism and viability. Metabolic profiling of SP-treated neurons established accumulation of α-ketoglutarate and pyruvate as indicators of the KGDHC inhibition and ensuing impairment of pyruvate oxidation in the tricarboxylic acid cycle. Concomitant increases in alanine, glutamate and λ-aminobutyrate indicated a scavenging of the accumulated pyruvate and α-ketoglutarate by transamination and further decarboxylation of glutamate. Changes among other amino acids were in accordance with their potential to react with α-ketoglutarate or products of its transamination and serve as fuel compensating for the KGDHC block. Disturbances in neuronal amino acid pool were accompanied by changed polyamines, decreased total protein and increased thymine, suggesting increased catabolism of amino acids to decrease translation and affect DNA turnover/repair. The ensuing ATP salvage was observed as the paradoxical increase in neuronal ATP by mitochondrial inhibitor SP. Extensive exposure of neurons to SP reduced viability, as revealed by both the ATP- and NAD(P)H-dependent viability tests. Thus, we provide experimental evidence on the KGDHC impairment as a cause of neurodegeneration and decipher underlying molecular mechanisms, exposing the key regulatory complex of the tricarboxylic acid cycle as a promising target for directed regulation of neuronal function and survival.
Keywords: Cellular models of neurodegeneration, metabolic engineering, metabolic profiling, mitochondria in neurodegenerative diseases, α-ketoglutarate dehydrogenase, succinyl phosphonate, tricarboxylic acid cycle.
Current Medicinal Chemistry
Title:Consequences of the α-Ketoglutarate Dehydrogenase Inhibition for Neuronal Metabolism and Survival: Implications for Neurodegenerative Diseases
Volume: 19 Issue: 34
Author(s): L. K. Trofimova, W. L. Araujo, A. A. Strokina, A. R. Fernie, L. Bettendorff and V. I. Bunik
Affiliation:
Keywords: Cellular models of neurodegeneration, metabolic engineering, metabolic profiling, mitochondria in neurodegenerative diseases, α-ketoglutarate dehydrogenase, succinyl phosphonate, tricarboxylic acid cycle.
Abstract: Neurodegenerative diseases are accompanied by reduced activity of mitochondrial α-ketoglutarate dehydrogenase multienzyme complex (KGDHC). We present a new cellular model to study molecular mechanisms of this association. By application of the highly specific and efficient inhibitor of KGDHC, succinyl phosphonate (SP), to cultured neurons, we characterized the concentrationand time-dependent consequences of decreased KGDHC activity for neuronal metabolism and viability. Metabolic profiling of SP-treated neurons established accumulation of α-ketoglutarate and pyruvate as indicators of the KGDHC inhibition and ensuing impairment of pyruvate oxidation in the tricarboxylic acid cycle. Concomitant increases in alanine, glutamate and λ-aminobutyrate indicated a scavenging of the accumulated pyruvate and α-ketoglutarate by transamination and further decarboxylation of glutamate. Changes among other amino acids were in accordance with their potential to react with α-ketoglutarate or products of its transamination and serve as fuel compensating for the KGDHC block. Disturbances in neuronal amino acid pool were accompanied by changed polyamines, decreased total protein and increased thymine, suggesting increased catabolism of amino acids to decrease translation and affect DNA turnover/repair. The ensuing ATP salvage was observed as the paradoxical increase in neuronal ATP by mitochondrial inhibitor SP. Extensive exposure of neurons to SP reduced viability, as revealed by both the ATP- and NAD(P)H-dependent viability tests. Thus, we provide experimental evidence on the KGDHC impairment as a cause of neurodegeneration and decipher underlying molecular mechanisms, exposing the key regulatory complex of the tricarboxylic acid cycle as a promising target for directed regulation of neuronal function and survival.
Export Options
About this article
Cite this article as:
K. Trofimova L., L. Araujo W., A. Strokina A., R. Fernie A., Bettendorff L. and I. Bunik V., Consequences of the α-Ketoglutarate Dehydrogenase Inhibition for Neuronal Metabolism and Survival: Implications for Neurodegenerative Diseases, Current Medicinal Chemistry 2012; 19 (34) . https://dx.doi.org/10.2174/092986712804143367
DOI https://dx.doi.org/10.2174/092986712804143367 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Pleiotropic Effects of ARB in Vascular Metabolism - Focusing on Atherosclerosis-Based Cardiovascular Disease
Current Vascular Pharmacology Difluorinated Curcumin: A Promising Curcumin Analogue with Improved Anti-Tumor Activity and Pharmacokinetic Profile
Current Pharmaceutical Design Mild Systemic Inflammation has a Neuroprotective Effect After Stroke in Rats
Current Neurovascular Research Current Signal Transduction Therapy for Brain Tumors Review Article
Current Signal Transduction Therapy From Antidepressant Drugs to Beta-Mimetics: Preclinical Insights on Potential New Treatments for Neuropathic Pain
Recent Patents on CNS Drug Discovery (Discontinued) Neuroretinal Apoptosis as a Vascular Dysfunction in Diabetic Patients
Current Neuropharmacology Biomarkers in Silent Traumatic Brain Injury
Current Pharmaceutical Design Calcium Sensitizers in Cardiac Surgery: Who, When, How and Why?
Current Vascular Pharmacology microRNAs-based Predictor Factor in Patients with Migraine-ischemic Stroke
MicroRNA Bioactivity of Marine Natural Product Xyloketals
Letters in Organic Chemistry Oxidative Stress and Pathophysiology of Ischemic Stroke: Novel Therapeutic Opportunities
CNS & Neurological Disorders - Drug Targets Role of the Sympathetic Nervous Activity in Hypertension-Update in 2013
Current Hypertension Reviews PPARγ-targeting Potential for Radioprotection
Current Drug Targets Pharmacological Modulation of Caspase Activation
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Fetal Programming of the Human Brain: Is there a Link with Insurgence of Neurodegenerative Disorders in Adulthood?
Current Medicinal Chemistry Current Biological Therapies for Inflammatory Bowel Disease
Current Pharmaceutical Design Glia: An Important Target for Anti-Inflammatory and Antidepressant Activity
Current Drug Targets Aquaporins and Neurodegenerative Diseases
Current Neuropharmacology Free Radicals in Diseases and Potential Role of Phytoconstituents-A Cause with Emerging Importance
Current Chemical Biology Carnitine Metabolism and Deficit - When Supplementation is Necessary?
Current Pharmaceutical Biotechnology