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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The yeast protein Ubx4p contributes to mitochondrial respiration and lithium?galactose?mediated activation of the unfolded protein response

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De-Souza, Evandro A. [1] ; Pimentel, Felipe S. A. [1] ; De-Queiroz, Ana Luiza F. V. [1] ; Camara, Henrique [2] ; Felix-Formiga, Mikaella L. [1] ; Machado, Caio M. [1] ; Pinto, Silas [2] ; Galina, Antonio [3] ; Mori, Marcelo A. [2] ; Montero-Lomeli, Monica [1] ; Masuda, Claudio A. [1]
Total Authors: 11
[1] Univ Fed Rio de Janeiro, Programa Biol Mol & Biotecnol, Inst Bioquim Med Leopoldo de Meis, BR-21941902 Rio De Janeiro - Brazil
[2] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Inst Biol, BR-13083970 Campinas, SP - Brazil
[3] Univ Fed Rio de Janeiro, Programa Bioquim & Biofis Celular, Inst Bioquim Med Leopoldo de Meis, BR-21941902 Rio De Janeiro - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Journal of Biological Chemistry; v. 295, n. 12, p. 3773-3782, MAR 20 2020.
Web of Science Citations: 0

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 ubx4? phenotype is ERAD-independent. We also observed that the ubx4? strain displays decreased oxygen consumption. The inhibition of mitochondrial respiration was sufficient to diminish galactose-1-phosphate levels and, consequently, affects UPR activation. Finally, we show that the deletion of the AMP-activated protein kinase ortholog?encoding gene SNF1 can restore the oxygen consumption rate in ubx4? 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. (AU)

FAPESP's process: 17/01184-9 - CAMeLEOm: cross-species analysis of metabolic, lifespan effects and omics of dietary restriction mimetics
Grantee:Marcelo Alves da Silva Mori
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/01339-2 - Uncovering mechanisms of longevity mediated by mobile RNAs
Grantee:Henrique Camara
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 17/04377-2 - Study of Dicer effects on mitochondrial function, metabolism and aging in c. elegans nematodes
Grantee:Silas Pinto da Silva
Support type: Scholarships in Brazil - Doctorate