The role of cardiolipin in longevity and stress response in Saccharomyces cerevisiae

Jingming Zhou, Wayne State University

Abstract

This work focused on the role of cardiolipin (CL), a mitochondrial phospholipid, in the aging process. Loss of CL leads to defective cell wall synthesis and mtDNA instability (Zhong et al., 2005), factors that are linked to aging. Based on this, I hypothesized that CL mutants exhibit shortened life spans. The replicative life span of yeast cardiolipin mutants demonstrated that perturbation of CL synthesis leads to decreased life span by mechanisms associated with cell wall integrity as well as mild stress, but not calorie restriction. In addition, restoration of cell integrity leads to increased life span, as promoting cell wall stability with the osmotic stabilizer sorbitol or by genetic suppression with kre5W1166X increases the life span of CL mutants. A targeted genetic screen for pgs1Δ suppressors demonstrated that downregulation of the high osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathway alleviated the temperature sensitivity and longevity defects of pgs1Δ, suggesting that activation of HOG is deleterious to pgs1Δ. Evidence indicated that Hog1p is over-activated in pgs1Δ, and that pgs1Δ did notexhibit cell cycle or vacuolar defects that can be associated with increased Hog1p activation. Therefore, normal activation of the HOG pathway is deleterious in the absence of CL synthesis. Further studies revealed that deletion of SHO1, an upstream sensor of the HOG pathway, rescued pgs1Δ defects, possibly by alleviating cell wall defects. These findings showed for the first time that mitochondrial anionic phospholipids are required for normal replicative life span, and the defective longevity caused by loss of the CL pathway can be alleviated by down-regulation of the HOG pathway or promotion of cell integrity. These findings suggest novel functions of CL in stress signaling, cell integrity, and aging regulation. Future studies that focus on how these processes are affected in CL mutants may help to understand the role of CL in cellular processes that are closely associated with aging and apoptosis and eventually lead to treatment of human diseases that are associated with perturbation of CL synthesis.

Recommended Citation

Jingming Zhou, "The role of cardiolipin in longevity and stress response in Saccharomyces cerevisiae" (January 1, 2009). ETD Collection for Wayne State University. Paper AAI3350058.
http://digitalcommons.wayne.edu/dissertations/AAI3350058