RRC ID 59430
Author Zhou J, Wang X, Wang M, Chang Y, Zhang F, Ban Z, Tang R, Gan Q, Wu S, Guo Y, Zhang Q, Wang F, Zhao L, Jing Y, Qian W, Wang G, Guo W, Yang C.
Title The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis.
Journal J Cell Biol
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.
Volume 218(2)
Pages 580-597
Published 2019-2-4
DOI 10.1083/jcb.201807204
PII jcb.201807204
PMID 30573525
PMC PMC6363459
MeSH Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Homeostasis* Hyperlysinemias / genetics Hyperlysinemias / metabolism Lysine / analogs & derivatives* Lysine / metabolism Mice Mitochondria, Liver* / genetics Mitochondria, Liver* / metabolism Mutation Saccharopine Dehydrogenases* / deficiency Saccharopine Dehydrogenases* / genetics Saccharopine Dehydrogenases* / metabolism
IF 8.891
Times Cited 7
C.elegans tm1133 tm1108