J Cell Biol. 20 december,2018|Supp Info:https://doi.org/10.1083/jcb.201807204

The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis

Junxiang Zhou^1,2,3, Xin Wang² , Min Wang¹, Yuwei Chang⁴, Fengxia Zhang⁴, Zhaonan Ban^3,4, Ruofeng Tang^1,3, Qiwen Gan^1,3, Shaohuan Wu^3,4,5, Ye Guo¹, Qian Zhang^1,3, Fengyang Wang^1,3, Liyuan Zhao^1,3, Yudong Jing¹ , Wenfeng Qian^4,5, Guodong Wang⁴, Weixiang Guo¹ , and Chonglin Yang^1,2

^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.