A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Abstract

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

Identification of lysine-lactylated substrates in gastric cancer cells

“…Alternative splicing increases the diversity of proteins by affecting the complexity of mRNA, and is known to regulate multiple cellular progress ( Zhang et al., 2021 ). It was previously reported that RNA splicing could affect lactate metabolism ( Klipfel et al., 2021 ; Leyva-Carrillo et al., 2019 ; Li et al., 2020b ); however, whether lactate could affect RNA splicing was unknown. We have identified 193 Kla sites in 70 spliceosome-related proteins.…”

The Emergence of the Metabolic Signaling of the Nucleoredoxin-like Genes during Evolution

“…The visual phenotype of the Bsg1 -/-v1 mouse may result from lactate accumulation in the outer retina (Ochrietor and Linser, 2004), as observed after deletion of the Bsg gene in the RPE at 4 weeks of age (Han et al, 2020). In the RPE, BSG2 is a chaperone for the lactate transporters MCT1 and MCT3 which mediate transepithelial transport from the subretinal space to the blood circulation of lactate, produced by the retina through aerobic glycolysis (Klipfel et al, 2021;Leveillard et al, 2019).…”

Transcriptome Sequencing Analysis of the Effect of β-Elemene on Colorectal Cancer from the lncRNA-miRNA-mRNA Perspective

“…Additionally, solute carrier family 16 member 8 (SLC16A8), alias MCT3 and REMP, belongs to a family of proton-coupled monocarboxylate transporters regulating lactate transport across cell membranes [31]. e study of Klipfel L demonstrates the loss of transport function of the hypomorphic allele in the SLC16A8 gene and offers a methodological framework for the investigation of other SLC16A8 alleles linked to age-related macular degeneration [32]. Currently, there are no reports about these two genes in CRC development.…”