Petit 2013 Abstract MiP2013
|Petit PX (2013) The cardiolipin defect linked to a tafazzin mutation in Barth syndrome disturbs mitochondrial metabolism, alters apoptosis and autophagic fluxes but does not affect cell cycle progression. Mitochondr Physiol Network 18.08.|
Petit PX (2013)
Cardiolipin (CL) is a key phospholipid involved in ATP generation. Since progression through the cell cycle requires ATP, we examined the regulation of CL synthesis during S-phase in human cells and investigated whether CL or CL synthesis was required to support nucleotide synthesis in S-phase. HeLa cells were made quiescent by serum depletion for 24 h. The addition of serum resulted in a substantial stimulation of [methyl-3H]thymidine incorporation into cells as compared to serum-starved cells by 8 h, confirming entry into the S-phase. CL mass was unaltered at 8 h, but increased 2-fold 16 h after addition of as compared to serum-starved cells. The increase in CL mass upon entry into S-phase resulted from an increase in the activity and the expression of CL de novo biosynthetic and remodelling enzymes and this paralleled the increase in mitochondrial mass. Barth Syndrome lymphoblasts or HeLa cells in which tafazzin was knocked down exhibit reduced CL (with acyl chain changes), a massive accumulation of monolysoCL and abnormal mitochondria. However, altered mitochondrial respiration appeared to be compensated for, at the cellular level, by an increase in mitochondrial mass as ascertained by citrate synthase activity and electron microscopy. These events are also described on Barth syndrome-derived lymphoblasts where we have shown that cardiolipin is required for apoptosis in the type II mitochondria dependent response to Fas stimulation, since apoptosis is completly abolished in the Barth syndrome-derived cells or the equivallent HeLa cell model used. Further, in Barth syndrome-derived lymphoblasts and an equivalent HeLa cell model, we have shown that cardiolipin is required for apoptosis in the type II mitochondria dependent response to Fas stimulation . These results provide the missing link between receptors at the plasma membrane and the mitochondria. Barth syndrome-derived lymphoblasts also exhibit a subtle increase in ROS production. We also show in these cells an increase in autophagic fluxes. However, these cells showed similar [methyl-3H]thymidine incorporation into cells upon serum addition to serum-starved cells as compared with cells from normal aged-matched controls. The cells passed through the cell cycle in a very similar fashion perhaps because the global level of ATP is similar to normal cells even though individual mitochondria may differ in their functional activities.
These results indicate that de novo CL biosynthesis is up-regulated via elevated activity and expression of CL biosynthetic genes and this accounts for the doubling of CL seen during S-phase. However, normal de novo CL biosynthesis or CL itself is not essential to support nucleotide synthesis during entry into S-phase of the human cell cycle.
• Keywords: Cell cycle, Barth syndrome
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mt-Structure;fission;fusion, mt-Membrane, mt-Medicine Pathology: Inherited Stress:Cell death Organism: Human Tissue;cell: Blood cells, Other cell lines, HeLa Preparation: Intact cells Enzyme: Marker enzyme
Coupling state: ROUTINE
Pharmacology, Experimental Toxicology and Cellular Signaling, CNRS / INSERM UMR S-747, Paris, France. - Email: email@example.com
- Gonzalvez F, D´Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauné-Pelloquin L, Vial G, Taleux N, Slomianny C, Wanders RJ, Houtkooper RH, Bellenguer P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX (2013) Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation. Biochim Biophys Acta 1832: 1194-1206.
- Gonzalvez F, Schug ZT, Houtkooper RH, Mackenzie ED, Brooks DG, Wanders RJ, Petit RJ, Vaz FM, Gottlieb E (2008) Cardiolipin provides an essential activating plateforme for caspase-8 on mitochondria. J Cell Biol 183: 681-696.