Apoptosis plays a critical role in several pathological processes, such as neurodegenerative diseases and various cardiovascular diseases. Besides, it is therefore not surprising that mitochondrial dysfunction is associated with various human diseases. Located at the outer mitochondrial membrane (OMM), 2 the voltage-dependent anion channel (VDAC) serves as a mitochondrial gatekeeper. Moreover, the outer mitochondrial membrane protein VDAC1 is a convergence point for a variety of cell survival and death signals, including apoptosis. Furthermore, VDAC1 oligomerization is involved in mitochondrion-mediated apoptosis. Thus, VDAC1 oligomerization represents a prime target for agents designed to modulate apoptosis. VDAC1 has acted as a key protein in mitochondrion-mediated apoptosis, regulating the release of apoptogenic proteins, as well as interacting with anti-apoptotic proteins. Meanwhile, targeting the oligomeric status of VDAC1, and hence apoptosis offers a strategy for combating cancers and neurodegenerative diseases. AKOS-22 is a potent mitochondrial protein VDAC1 and apoptosis inhibitor and protects against Mitochondrial Dysfunction.
AKOS-22 is a potent mitochondrial protein VDAC1 inhibitor (Kd=15.4 μM). Specifically, AKOS-22 interacts with VDAC1 and inhibiting both VDAC1 oligomerization and apoptosis. Nonetheless, AKOS-22 protects against mitochondrial dysfunction. Additionally, AKOS-22 inhibited both VDAC1 oligomerization and apoptosis in a concentration-dependent manner, with 50% inhibition of both apoptosis and VDAC1 oligomerization. In addition to inhibition of apoptosis, AKOS-022 prevented the elevation of [Ca2+]i associated with apoptosis induction, and thus Ca2+ accumulation by the mitochondria. Finally, the linear relationship between inhibition of VDAC1 oligomerization and inhibition of apoptosis by AKOS-022 offers further support. It is for the involvement of VDAC1 oligomerization in the induction of apoptosis. All in all, AKOS-22 is a potent mitochondrial protein VDAC1 inhibitor and interacts with VDAC1 and inhibiting both VDAC1 oligomerization and apoptosis.
References:
Ben-Hail D, et al. J Biol Chem. 2016 Nov 25;291(48):24986-25003.