Tricarboxylic acid cycle activity suppresses acetylation of mitochondrial proteins during early embryonic development in Caenorhabditis elegans
| Autor: | Masaki Matsumoto, Keiko Hirota, Reiya Ohta, Hiroaki Daitoku, Sho Araoi, Ai Inanobe, Toshikatsu Hanada, Akiyoshi Fukamizu, Koichiro Kako, Mitsuhiro Arisawa, Kazumasa Hada, Mai Miyata |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Time Factors Citric Acid Cycle Intracellular Space Embryonic Development Glutamic Acid Citrate (si)-Synthase Mitochondrion Biochemistry Citric Acid Mitochondrial Proteins 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Animals Citrate synthase Caenorhabditis elegans Molecular Biology chemistry.chemical_classification Aspartic Acid 030102 biochemistry & molecular biology biology Acetylation Cell Biology biology.organism_classification Amino acid Cell biology Spermidine Citric acid cycle Metabolism 030104 developmental biology chemistry biology.protein Putrescine Polyamine |
| Zdroj: | Journal of Biological Chemistry. 294:3091-3099 |
| ISSN: | 0021-9258 |
| Popis: | The tricarboxylic acid (TCA) cycle (or citric acid cycle) is responsible for the complete oxidation of acetyl-CoA and formation of intermediates required for ATP production and other anabolic pathways, such as amino acid synthesis. Here, we uncovered an additional mechanism that may help explain the essential role of the TCA cycle in the early embryogenesis of Caenorhabditis elegans. We found that knockdown of citrate synthase (cts-1), the initial and rate-limiting enzyme of the TCA cycle, results in early embryonic arrest, but that this phenotype is not because of ATP and amino acid depletions. As a possible alternative mechanism explaining this developmental deficiency, we observed that cts-1 RNAi embryos had elevated levels of intracellular acetyl-CoA, the starting metabolite of the TCA cycle. Of note, we further discovered that these embryos exhibit hyperacetylation of mitochondrial proteins. We found that supplementation with acetylase-inhibiting polyamines, including spermidine and putrescine, counteracted the protein hyperacetylation and developmental arrest in the cts-1 RNAi embryos. Contrary to the hypothesis that spermidine acts as an acetyl sink for elevated acetyl-CoA, the levels of three forms of acetylspermidine, N(1)-acetylspermidine, N(8)-acetylspermidine, and N(1),N(8)-diacetylspermidine, were not significantly increased in embryos treated with exogenous spermidine. Instead, we demonstrated that the mitochondrial deacetylase sirtuin 4 (encoded by the sir-2.2 gene) is required for spermidine's suppression of protein hyperacetylation and developmental arrest in the cts-1 RNAi embryos. Taken together, these results suggest the possibility that during early embryogenesis, acetyl-CoA consumption by the TCA cycle in C. elegans prevents protein hyperacetylation and thereby protects mitochondrial function. |
| Databáze: | OpenAIRE |
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