The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis
| Autor: | Fengyang Wang, Yuwei Chang, Fengxia Zhang, Qiwen Gan, Min Wang, Guodong Wang, Zhaonan Ban, Chonglin Yang, Weixiang Guo, Yudong Jing, Shaohuan Wu, Xin Wang, Ye Guo, Wenfeng Qian, Ruofeng Tang, Liyuan Zhao, Junxiang Zhou, Qian Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
Hyperlysinemia
Mitochondria Liver Saccharomyces cerevisiae Biology Mitochondrion complex mixtures Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Commentaries Hyperlysinemias medicine Animals Homeostasis Spotlight Caenorhabditis elegans Caenorhabditis elegans Proteins Research Articles 030304 developmental biology 0303 health sciences ATP synthase Catabolism Lysine Saccharopine dehydrogenase Cell Biology medicine.disease Mitochondria Cell biology Mitochondrial toxicity chemistry Saccharopine Saccharopinuria Mutation biology.protein bacteria Saccharopine Dehydrogenases 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Defective lysine catabolism leads to two types of hyperlysinemia, but the mechanisms are unclear. Zhou et al. reveal that accumulation of saccharopine, an intermediate of lysine catabolism, leads to defective development of Caenorhbditis elegans and mice and that this correlates with disrupted mitochondrial dynamics, damage, and functional loss. 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. |
| Databáze: | OpenAIRE |
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