論文 - 詳細
| RRC ID | 76097 |
|---|---|
| 著者 | Yang Q, Liu P, Anderson NS, Shpilka T, Du Y, Naresh NU, Li R, Zhu LJ, Luk K, Lavelle J, Zeinert RD, Chien P, Wolfe SA, Haynes CM. |
| タイトル | LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria. |
| ジャーナル | Nat Cell Biol |
| Abstract |
The accumulation of deleterious mitochondrial DNA (∆mtDNA) causes inherited mitochondrial diseases and ageing-associated decline in mitochondrial functions such as oxidative phosphorylation. Following mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcriptional programme to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ∆mtDNAs in heteroplasmic worms. The mechanism by which ATFS-1 promotes ∆mtDNA accumulation relative to wild-type mtDNAs is unclear. Here we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria owing to degradation by the mtDNA-bound protease LONP-1, which results in the nearly exclusive association between ATFS-1 and ∆mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to ∆mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wild-type mtDNAs. LONP-1 inhibition in Caenorhabditis elegans and human cybrid cells improved the heteroplasmy ratio and restored oxidative phosphorylation. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1. |
| 巻・号 | 24(2) |
| ページ | 181-193 |
| 公開日 | 2022-2-1 |
| DOI | 10.1038/s41556-021-00840-5 |
| PII | 10.1038/s41556-021-00840-5 |
| PMID | 35165413 |
| PMC | PMC8868506 |
| MeSH | ATP-Dependent Proteases* / genetics ATP-Dependent Proteases* / metabolism Animals Animals, Genetically Modified Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Cell Line DNA Polymerase gamma / genetics DNA Polymerase gamma / metabolism DNA Replication* DNA, Mitochondrial* / biosynthesis DNA, Mitochondrial* / genetics Heteroplasmy* Humans Mitochondria* / genetics Mitochondria* / metabolism Mitochondria* / pathology Mitochondrial Proteins* / genetics Mitochondrial Proteins* / metabolism Oxidative Phosphorylation* Proteolysis Transcription Factors* / genetics Transcription Factors* / metabolism |
| 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 | 54 |
| 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 | tm598 |