title: Inhibition of stress mediated cell death by human lactate dehydrogenase B in yeast.
abstract: We report the identification of human L- lactate dehydrogenase B (LDHB) as a novel Bax suppressor. Yeast heterologously expressing LDHB is also resistant to the lethal effects of copper indicating that it is a general suppressor of stress mediated cell death. To identify potential LDHB targets, LDHB was expressed in yeast mutants defective in apoptosis, necrosis and autophagy. The absence of functional PCD regulators including MCA1, YBH3, cyclophilin (CPR3) and VMA3, as well as the absence of the pro-survival autophagic pathway (ATG1,7) did not interfere with the LDHB mediated protection against copper indicating that LDHB functions independently of known PCD regulators or by simply blocking or stimulating a common PCD promoting or inhibitory pathway. Measurements of lactate levels revealed that short-term copper stress (1.6 mM, 4 h), does not increase intracellular levels of lactate, instead a three-fold increase in extracellular lactate was observed. Thus, yeast cells resemble mammalian cells where different stresses are known to lead to increased lactate production leading to lactic acidosis. In agreement with this, we found that the addition of exogenous lactic acid to growth media was sufficient to induce cell death that could be inhibited by the expression of LDHB. Taken together our results suggest that lactate dehydrogenase is a general suppressor of PCD in yeast.
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec.
authors.forename: Sara
authors.initials: S
authors.lastname: Sheibani
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Jones
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario Biology Department, Queen's University, Kingston, Ontario.
authors.forename: Rawan
authors.initials: R
authors.lastname: Eid
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario.
authors.forename: Nada
authors.initials: N
authors.lastname: Gharib
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario Biology Department, Queen's University, Kingston, Ontario.
authors.forename: Nagla T T
authors.initials: NT
authors.lastname: Arab
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Titorenko
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec.
authors.forename: Hojatollah
authors.initials: H
authors.lastname: Vali
authors.affiliation: Biology Department, Queen's University, Kingston, Ontario.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Young
authors.affiliation: Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario michael.greenwood@rmc.ca.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Greenwood
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D019344:Lactic Acid / Q000494:pharmacology; D009336:Necrosis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
chemical_list: D007527:Isoenzymes; D051028:bcl-2-Associated X Protein; D019344:Lactic Acid; D003300:Copper; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1
keywords: LDHB; anti-apoptosis; apoptosis; cell survival; lactate; programmed cell death