Beach 2013 Abstract MiP2013
|Beach A, Richard VR, Leonov A, Burstein MT, Feldman R, Gentile C, Titorenko VI (2013) Lithocholic acid delays aging in yeast and exhibits an anti-tumor effect in human cells by altering mitochondrial composition, structure and function. Mitochondr Physiol Network 18.08.|
We use the yeast Saccharomyces cerevisiae as a model to study the molecular mechanisms by which age-related changes in mitochondrial membrane lipids regulate longevity [1-8].
We found that an exogenously added bile acid called lithocholic acid (LCA) extends yeast chronological lifespan and accumulates in the inner mitochondrial membrane (IMM). To define the mechanism by which LCA extends yeast longevity, we 1) examined how LCA influences mitochondrial proteome and lipidome; 2) investigated the effect of LCA on the composition and stoichiometry of respiratory complexes and supercomplexes in the IMM; 3) assessed how LCA affects mitochondrial oxygen consumption, membrane potential and reactive oxygen species (ROS); 4) examined how LCA influences mitochondrial morphology and how it affects the chronology of events characteristic of age-related, mitochondria-controlled apoptosis; and 5) investigated the effect of LCA on the lifespans of long- and short-lived mutants lacking individual components of the mitochondrial fission and fusion machines.
Our findings imply that LCA delays yeast aging by increasing the level of phosphatidylserine (PS) and decreasing the levels of phosphatidylethanolamine (PE) and cardiolipin in the IMM. By altering the abundance of these lipid species, LCA greatly expands mitochondrial membrane cristae. In addition, LCA enhances the positive effect of PS and weakens the negative effect of PE on membrane protein machines whose activity they modulate – thereby 1) stimulating protein machines driving mitochondrial respiration, the maintenance of mitochondrial membrane potential and ROS homeostasis, and mitochondrial fusion; and 2) inhibiting protein machines promoting mitochondrial fission and mitochondria-controlled apoptosis.
We found that LCA also functions as a potent and selective anti-tumor compound in cultured human neuroblastoma, glioma and breast cancer cells by modulating mitochondrial processes playing essential roles in both cancer and aging. The effects of LCA on these processes seen in cancer cell cultures are opposite of those observed in non-cancerous human cells and in chronologically aged, quiescent yeast.
Labels: MiParea: Respiration, mt-Structure;fission;fusion, mt-Membrane, mt-Medicine Pathology: Aging;senescence, Cancer Stress:Cell death, Oxidative stress;RONS Organism: Human, Saccharomyces cerevisiae Tissue;cell: Other cell lines, Neuroblastoma Preparation: Intact cells Enzyme: Supercomplex Regulation: mt-Membrane potential
Dept of Biology, Concordia University, Montreal, Canada. - Email: [email protected]
Supported by the Natural Science and Engineering Research Council of Canada (NSERC), and Concordia University Chair Fund. Adam Beach and Vincent R. Richard are supported by doctoral scholarships from the CIHR. V.I. Titorenko is a Concordia University Research Chair in Genomics, Cell Biology and Aging.
- Goldberg AA, Bourque SD, Kyryakov P, Gregg C, Boukh-Viner T, Beach A, Burstein MT, Machkalyan G, Richard V, Rampersad S, Cyr D, Milijevic S, Titorenko VI (2009) Effect of calorie restriction on the metabolic history of chronologically aging yeast. Exp Gerontol 44: 555-571.
- Goldberg AA, Richard VR, Kyryakov P, Bourque SD, Beach A, Burstein MT, Glebov A, Koupaki O, Boukh-Viner T, Gregg C, Juneau M, English AM, Thomas DY, Titorenko VI (2010) Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging 2: 393-414.
- Beach A, Titorenko VI (2011) In search of housekeeping pathways that regulate longevity. Cell Cycle 10: 3042-3044.
- Goldberg AA, Beach A, Davies GF, Harkness TAA, LeBlanc A, Titorenko VI (2011) Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget 2: 761-782.
- Kyryakov P, Beach A, Richard VR, Burstein MT, Leonov A, Levy S, Titorenko VI (2012) Caloric restriction extends yeast chronological lifespan by altering a pattern of age-related changes in trehalose concentration. Front Physiol 3: 256.
- Beach A, Burstein MT, Richard VR, Leonov A, Levy S, Titorenko VI (2012) Integration of peroxisomes into an endomembrane system that governs cellular aging. Front Physiol 3: 283.
- Burstein MT, Kyryakov P, Beach A, Richard VR, Koupaki O, Gomez-Perez A, Leonov A, Levy S, Noohi F, Titorenko VI (2012) Lithocholic acid extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan. Cell Cycle 11: 3443-3462.
- Beach A, Burstein MT, Richard VR, Gomez-Perez A, Leonov A, Iouk T, Titorenko VI (2013) A modular network regulates longevity of chronologically aging yeast. Cell Biol Res Ther 2: 1000e110.