論文 - 詳細
| RRC ID | 76347 |
|---|---|
| 著者 | Zhou J, Duan M, Wang X, Zhang F, Zhou H, Ma T, Yin Q, Zhang J, Tian F, Wang G, Yang C. |
| タイトル | A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology. |
| ジャーナル | Nat Cell Biol |
| Abstract |
D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP. |
| 巻・号 | 24(4) |
| ページ | 526-537 |
| 公開日 | 2022-4-1 |
| DOI | 10.1038/s41556-022-00883-2 |
| PII | 10.1038/s41556-022-00883-2 |
| PMID | 35418624 |
| MeSH | Brain Diseases, Metabolic, Inborn* / metabolism Feedback Glutarates / metabolism Humans Isocitrate Dehydrogenase / metabolism Mitochondria / metabolism Oxidoreductases Propionates* / metabolism |
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 44 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
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