S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons
Copyright © 2023 Elsevier Ltd. All rights reserved..
A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Cell chemical biology - 30(2023), 8 vom: 17. Aug., Seite 965-975.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Doulias, Paschalis-Thomas [VerfasserIn] |
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Date Completed 21.08.2023 Date Revised 09.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2023.06.018 |
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| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure | ||
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| 700 | 1 | |a Yang, Hongmei |e verfasserin |4 aut | |
| 700 | 1 | |a Andreyev, Alexander Y |e verfasserin |4 aut | |
| 700 | 1 | |a Dolatabadi, Nima |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Henry |e verfasserin |4 aut | |
| 700 | 1 | |a K Raspur, Charlene |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Parth R |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Tomohiro |e verfasserin |4 aut | |
| 700 | 1 | |a Tannenbaum, Steven R |e verfasserin |4 aut | |
| 700 | 1 | |a Ischiropoulos, Harry |e verfasserin |4 aut | |
| 700 | 1 | |a Lipton, Stuart A |e verfasserin |4 aut | |
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