Mysteries Surrounding ABT-199 That Stunned Us All

This work was supported by the Agence Nationale de la Recherche (Young Investigator Program Award No. JC08-317536 to A.R. and G.C.), Human Frontier Science Program Career Development Award No. 0061/2008 (to A.R.), Young Investigator Research Grant No. RGY0076/2009-C (to A.R.), Swiss National Fund for Research Grant?No. 31003A-130520/1 (to A.R.), the Soci��t�� Acad��mique de Gen��ve, and the Swiss National Centre for Competence in Research Programme Chemical Biology. L.D. acknowledges financial support from Grant ENFASIS (FIS2011-22644, from the Spanish Government). ""Mitochondrial Ca2+ homeostasis plays important Bcl-2 inhibitor roles in cellular physiology. Ca2+ flux across the inner mitochondrial membrane (IMM) regulates cell bioenergetics, cytoplasmic Ca2+ ([Ca2+]i) signals, and activation of cell death pathways (Balaban, 2009; Denton and McCormack, 1980; Duchen et?al., 2008; Gunter and Gunter, 1994; Hajn��czky et?al., 1995; Hansford, 1994; Herrington et?al., 1996; Lemasters et?al., 2009; McCormack et?al., 1990; Orrenius et?al., 2003; Szalai et?al., 1999). Mitochondrial Ca2+ (Ca2+m) uptake has been studied for more than five decades, with crucial insights into the underlying mechanisms enabled by development of the chemiosmotic hypothesis and appreciation of the considerable voltage across the IMM (����m) generated by proton Selleckchem ABT199 pumping in the respiratory chain (Carafoli, 1987; Drago et?al., 2011; Nicholls, 2005; O��Rourke, 2007; Rottenberg and Scarpa, 1974). Ca2+ uptake is an electrogenic process driven by ����m and mediated by a Ca2+-selective ion channel (MiCa; Kirichok et?al., 2004) called the uniporter (Bernardi, 1999; Igbavboa and Pfeiffer, 1988; O��Rourke, 2007; Santo-Domingo and Demaurex, 2010). Properties Bumetanide of the uniporter have been derived primarily from studies of isolated mitochondria, where it was generally found to have a low apparent Ca2+ affinity (10�C70?��M) with variable cooperativity (Bragadin et?al., 1979; Gunter et?al., 1994). Agonist-induced [Ca2+]i signals can be rapidly transduced to the mitochondrial matrix despite this apparent low affinity because mitochondria can exist in close apposition to sites of Ca2+ release where local [Ca2+]i can be higher than in the bulk cytoplasm (Carafoli and Lehninger, 1971; Collins et?al., 2001; Filippin et?al., 2003; Nicholls, 2008; Palmer et?al., 2006; Rizzuto et?al., 1998, 2004). Nevertheless, higher-affinity mitochondrial Ca2+ uptake has been observed in many studies (Santo-Domingo and Demaurex, 2010; Sp?t et?al., 2008). Furthermore, patch-clamp electrophysiology suggests that the uniporter pore has high Ca2+ affinity (dissociation constant