論文 - 詳細
| RRC ID | 59430 |
|---|---|
| 著者 | Zhou J, Wang X, Wang M, Chang Y, Zhang F, Ban Z, Tang R, Gan Q, Wu S, Guo Y, Zhang Q, Wang F, Zhao L, Jing Y, Qian W, Wang G, Guo W, Yang C. |
| タイトル | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis. |
| ジャーナル | J Cell Biol |
| Abstract |
Amino acid catabolism is frequently executed in mitochondria; however, it is largely unknown how aberrant amino acid metabolism affects mitochondria. Here we report the requirement for mitochondrial saccharopine degradation in mitochondrial homeostasis and animal development. In Caenorhbditis elegans, mutations in the saccharopine dehydrogenase (SDH) domain of the bi-functional enzyme α-aminoadipic semialdehyde synthase AASS-1 greatly elevate the lysine catabolic intermediate saccharopine, which causes mitochondrial damage by disrupting mitochondrial dynamics, leading to reduced adult animal growth. In mice, failure of mitochondrial saccharopine oxidation causes lethal mitochondrial damage in the liver, leading to postnatal developmental retardation and death. Importantly, genetic inactivation of genes that raise the mitochondrial saccharopine precursors lysine and α-ketoglutarate strongly suppresses SDH mutation-induced saccharopine accumulation and mitochondrial abnormalities in C. elegans Thus, adequate saccharopine catabolism is essential for mitochondrial homeostasis. Our study provides mechanistic and therapeutic insights for understanding and treating hyperlysinemia II (saccharopinuria), an aminoacidopathy with severe developmental defects. |
| 巻・号 | 218(2) |
| ページ | 580-597 |
| 公開日 | 2019-2-4 |
| DOI | 10.1083/jcb.201807204 |
| PII | jcb.201807204 |
| PMID | 30573525 |
| PMC | PMC6363459 |
| MeSH | Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Homeostasis* Hyperlysinemias / genetics Hyperlysinemias / metabolism Lysine / analogs & derivatives* Lysine / metabolism Mice Mitochondria, Liver* / genetics Mitochondria, Liver* / metabolism Mutation Saccharopine Dehydrogenases* / deficiency Saccharopine Dehydrogenases* / genetics Saccharopine Dehydrogenases* / metabolism |
| IF | 8.891 |
| 引用数 | 7 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 51 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm1133 tm1108 |