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.

ORCID IDs: 0000-0001-6777-6565 (M.E.S.); 0000-0001-9917-0656 (G.W.)The glycosylation of nicotinate (NA), a key intermediate of the NAD salvage pathway, occurs widely in land plants. However, the physiological function of NA glycosylation is not well understood in planta, and no gene encoding NA glycosyltransferase has been reported to date. NA glycosylation in Arabidopsis thaliana occurs at either the N-or the O-position of the NA molecule, and O-glucosylation appears to be unique to the Brassicaceae. Using gene-enzyme correlations focused on Family 1 glycosyltransferases (GTs; EC 2.4), we identified and characterized three Arabidopsis GTs, which are likely involved in NA glycosylation. These include one NAOGT (UGT74F2; previously identified as a salicylic acid glycosyltransferases) and two NANGTs (UGT76C4 and UGT76C5). Arabidopsis mutants of UGT74F2 accumulate higher levels of free NA, but not salicylic acid, than that of the wild type, and this inversely correlated with seed germination rates under various abiotic stresses. The germination defect of the ugt74f2-1 mutant could be fully complemented by overexpression of UGT74F2. These observations, together with comprehensive chemical analysis, suggest that NA glycosylation may function to protect plant cells from the toxicity of NA overaccumulation during seed germination. Combined with phylogenetic analysis, our results suggest that NAOGTs arose recently in the Brassicaceae family and may provide a fitness benefit. The multifunctionality of UGT74F2 in Arabidopsis is also investigated and discussed.