PUBLICATION

Slc38a9 Deficiency Induces Apoptosis and Metabolic Dysregulation and Leads to Premature Death in Zebrafish

Authors

Wu, X., Chen, J., Liu, C., Wang, X., Zhou, H., Mai, K., He, G.

ID

ZDB-PUB-220424-16

Date

2022

Source

International Journal of Molecular Sciences 23(8): (Journal)

Registered Authors

Liu, Chengdong

Keywords

SLC38A9, amino acid homeostasis, apoptosis, glycolysis, hypoxia

MeSH Terms

Animals
Amino Acids/metabolism
Amino Acid Transport Systems/metabolism
Zebrafish*/genetics
Zebrafish*/metabolism
Mortality, Premature*
Apoptosis/genetics

(all 7)

PubMed

35457018 Full text @ Int. J. Mol. Sci.

Abstract

Eukaryotic cells control nutritional homeostasis and determine cell metabolic fate through a series of nutrient transporters and metabolic regulation pathways. Lysosomal localized amino acid transporter member 9 of the solute carrier family 38 (SLC38A9) regulates essential amino acids' efflux from lysosomes in an arginine-regulated fashion. To better understand the physiological role of SLC38A9, we first described the spatiotemporal expression pattern of the slc38a9 gene in zebrafish. A quarter of slc38a9^-/- mutant embryos developed pericardial edema and died prematurely, while the remaining mutants were viable and grew normally. By profiling the transcriptome of the abnormally developed embryos using RNA-seq, we identified increased apoptosis, dysregulated amino acid metabolism, and glycolysis/gluconeogenesis disorders that occurred in slc38a9^-/- mutant fish. slc38a9 deficiency increased whole-body free amino acid and lactate levels but reduced glucose and pyruvate levels. The change of glycolysis-related metabolites in viable slc38a9^-/- mutant fish was ameliorated. Moreover, loss of slc38a9 resulted in a significant reduction in hypoxia-inducible gene expression and hypoxia-inducible factor 1-alpha (Hif1α) protein levels. These results improved our understanding of the physiological functions of SLC38A9 and revealed its indispensable role in embryonic development, metabolic regulation, and stress adaption.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	hypoxia	Pec-fin	eye decreased size, abnormal	Figure 7
WT	hypoxia	Pec-fin	pericardium edematous, abnormal	Figure 7
WT	hypoxia	Pec-fin	whole organism ddit4 expression increased amount, abnormal	Figure 7
WT	hypoxia	Pec-fin	whole organism igfbp1a expression increased amount, abnormal	Figure 7
WT	hypoxia	Pec-fin	whole organism Ab6-hif1a labeling increased amount, abnormal	Figure 7
WT	hypoxia	Pec-fin	whole organism decreased length, abnormal	Figure 7
slc38a9^{ouc101/ouc101}	standard conditions	5-9 somites	whole organism morphology, normal	Figure 2
slc38a9^{ouc101/ouc101}	standard conditions	Prim-5	whole organism decreased length, abnormal	Figure 2
slc38a9^{ouc101/ouc101}	standard conditions	Prim-5	whole organism morphology, normal	Figure 2
slc38a9^{ouc101/ouc101}	standard conditions	Long-pec	eye decreased size, abnormal	Figure 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ouc101		Small Deletion	slc38a9
ouc102		Small Deletion	slc38a9

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
slc38a9	CRISPR1-slc38a9	CRISPR

Fish

Fish
slc38a9^{ouc101/ouc101}
slc38a9^{ouc102/ouc102}
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab6-hif1a	polyclonal		IgG	Rabbit

Orthology

Engineered Foreign Genes

Mapping

Wu et al., 2022 ZDB-PUB-220424-16 PMID:35457018

Slc38a9 Deficiency Induces Apoptosis and Metabolic Dysregulation and Leads to Premature Death in Zebrafish

Wu et al., 2022

ZDB-PUB-220424-16
PMID:35457018