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The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis
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 elegan...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363459/ https://www.ncbi.nlm.nih.gov/pubmed/30573525 http://dx.doi.org/10.1083/jcb.201807204 |
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author | Zhou, Junxiang Wang, Xin Wang, Min Chang, Yuwei Zhang, Fengxia Ban, Zhaonan Tang, Ruofeng Gan, Qiwen Wu, Shaohuan Guo, Ye Zhang, Qian Wang, Fengyang Zhao, Liyuan Jing, Yudong Qian, Wenfeng Wang, Guodong Guo, Weixiang Yang, Chonglin |
author_facet | Zhou, Junxiang Wang, Xin Wang, Min Chang, Yuwei Zhang, Fengxia Ban, Zhaonan Tang, Ruofeng Gan, Qiwen Wu, Shaohuan Guo, Ye Zhang, Qian Wang, Fengyang Zhao, Liyuan Jing, Yudong Qian, Wenfeng Wang, Guodong Guo, Weixiang Yang, Chonglin |
author_sort | Zhou, Junxiang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6363459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63634592019-08-04 The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis Zhou, Junxiang Wang, Xin Wang, Min Chang, Yuwei Zhang, Fengxia Ban, Zhaonan Tang, Ruofeng Gan, Qiwen Wu, Shaohuan Guo, Ye Zhang, Qian Wang, Fengyang Zhao, Liyuan Jing, Yudong Qian, Wenfeng Wang, Guodong Guo, Weixiang Yang, Chonglin J Cell Biol Research Articles 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. Rockefeller University Press 2019-02-04 /pmc/articles/PMC6363459/ /pubmed/30573525 http://dx.doi.org/10.1083/jcb.201807204 Text en © 2019 Zhou et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Zhou, Junxiang Wang, Xin Wang, Min Chang, Yuwei Zhang, Fengxia Ban, Zhaonan Tang, Ruofeng Gan, Qiwen Wu, Shaohuan Guo, Ye Zhang, Qian Wang, Fengyang Zhao, Liyuan Jing, Yudong Qian, Wenfeng Wang, Guodong Guo, Weixiang Yang, Chonglin The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title_full | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title_fullStr | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title_full_unstemmed | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title_short | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
title_sort | lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363459/ https://www.ncbi.nlm.nih.gov/pubmed/30573525 http://dx.doi.org/10.1083/jcb.201807204 |
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