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  3. The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis

The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis

  • J Cell Biol. 2019 Feb 4;218(2):580-597. doi: 10.1083/jcb.201807204.
Junxiang Zhou 1 2 3,  Xin Wang 2,  Min Wang 1,  Yuwei Chang 4,  Fengxia Zhang 4,  Zhaonan Ban 3 4,  Ruofeng Tang 1 3,  Qiwen Gan 1 3,  Shaohuan Wu 3 4 5,  Ye Guo 1,  Qian Zhang 1 3,  Fengyang Wang 1 3,  Liyuan Zhao 1 3,  Yudong Jing 1,  Wenfeng Qian 4 5,  Guodong Wang 4,  Weixiang Guo 6,  Chonglin Yang 7 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 2 State Key Laboratory of Natural Resource Conservation and Utilization in Yunnan and Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
  • 3 Graduate University of Chinese Academy of Sciences, Beijing, China.
  • 4 State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 5 Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 6 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China wxguo@genetics.ac.cn.
  • 7 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China clyang@genetics.ac.cn.
PMID: 30573525 DOI: 10.1083/jcb.201807204
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.

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