De-Souza 2020 J Biol Chem
|De-Souza EA, Pimentel FSA, De-Queiroz ALFV, Camara H, Felix-Formiga ML, Machado CM, Pinto S, Galina A, Mori MA, Montero-Lomelí M, Masuda CA (2020) The yeast protein Ubx4p contributes to mitochondrial respiration and lithium-galactose-mediated activation of the unfolded protein response. J Biol Chem [Epub ahead of print].|
Abstract: In the presence of galactose, lithium ions activate the unfolded protein response (UPR) by inhibiting phosphoglucomutase activity and causing the accumulation of galactose-related metabolites, including galactose-1-phosphate. These metabolites also accumulate in humans who have the disease classic galactosemia. Here, we demonstrate that Saccharomyces cerevisiae yeast strains harboring a deletion of UBX4 - a gene encoding a partner of Cdc48p in the endoplasmic reticulum-associated degradation (ERAD) pathway - exhibit delayed UPR activation after lithium and galactose exposure because the deletion decreases galactose-1-phosphate levels. The delay in UPR activation did not occur in yeast strains in which key ERAD or proteasomal pathway genes had been disrupted, indicating that the ubx4Δ phenotype is ERAD-independent. We also observed that the ubx4Δ strain displays decreased oxygen consumption. The inhibition of mitochondrial respiration was sufficient to diminish galactose-1-phosphate levels and, consequently, affect UPR activation. Finally, we show that the deletion of the AMP-activated protein kinase (AMPK) ortholog-encoding gene SNF1 can restore the oxygen consumption rate in ubx4Δ strain, thereby reestablishing galactose metabolism, UPR activation, and cellular adaption to lithium-galactose challenge. Our results indicate a role for Ubx4p in yeast mitochondrial function and highlight that mitochondrial and endoplasmic reticulum functions are intertwined through galactose metabolism. These findings also shed new light on the mechanisms of lithium action and on the pathophysiology of galactosemia.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
• Keywords: ASPS-1, ASPSCR1, Caenorhabditis elegans (C. elegans), Saccharomyces cerevisiae, Endoplasmic reticulum stress (ER stress), Endoplasmic-reticulum-associated protein degradation (ERAD), Galactose, Galactosemia, Lithium, Mitochondria • Bioblast editor: Plangger M • O2k-Network Lab: BR Rio de Janeiro Galina A, BR Rio de Janeiro Institute Biomedical Chemistry
Labels: MiParea: Respiration, nDNA;cell genetics
Organism: Caenorhabditis elegans, Saccharomyces cerevisiae
Preparation: Isolated mitochondria, Intact cells
Coupling state: LEAK, OXPHOS Pathway: N, Gp, NS, ROX HRR: Oxygraph-2k