Effect of Inhibitors | Mechanism | Reference |
---|---|---|
Direct action via MPTP components | ||
CsA and its analogs (6-MeAla-CsA, 4-MeVal-CsA, N-Me-4-Ile-CsA (NIM811), d-3-MeAla-4-EtVal-CsA (Debio-025) | Inhibit CyP-D binding to PiC (ANT?) | Nazareth et al., 1991; Griffiths and Halestrap, 1993; Hausenloy et al., 2003; Argaud et al., 2005a,b; Gomez et al., 2007 |
SfA | Inhibits PPIase activity of CyP-D | Clarke et al., 2002; Hausenloy et al., 2003; Javadov et al., 2003; Lim et al., 2007 |
BKA and ADP | Induces “m” conformation of ANT | Halestrap and Davidson, 1990; Halestrap and Brennerb, 2003 |
H+ and divalent cations (Mg2+, Mn2+, Sr2+, Ba2+) | Antagonize Ca2+ binding to ANT | Haworth and Hunter, 1979; Bernardi et al., 1992 |
Indirect action MPTP opening | ||
ROS scavengers (e.g., propofol, pyruvate, MCI-186) | Prevent ROS accumulation and therefore oxidation of the critical thiol groups on the ANT | Kerr et al., 1999; Javadov et al., 2000; Rajesh et al., 2003 |
Low pHi inducers (NHE-1 inhibitor cariporide and analog pyruvate) | Reduce pHi that inhibits Ca2+ binding to ANT | Kerr et al., 1999; Teshima et al., 2003; Javadov et al., 2005, 2008 |
Ubiquinone analogs (e.g., UQ0, Ro 68–3400) | Unknown. May act via complex I or bind to ANT and PiC | Cesura et al., 2003; Krauskopf et al., 2006; Leung et al., 2008 |
Preconditioning/postconditioning | Prevent oxidative stress, normalize mitochondrial metabolism | Hausenloy et al., 2002; Javadov et al., 2003; Argaud et al., 2004, 2005b; Lim et al., 2007 |