, 2011 and Jin et al., 2010). As an aside, like PINK1, OPA1 also has long and short forms, with OPA1-L cleaved, not by PARL, but by AFG3L2, to produce http://www.selleckchem.com/products/BKM-120.html OPA1-S (Duvezin-Caubet et al., 2007). The long forms of both OPA1 and PINK1 are targeted to the inner membrane, where cleavage occurs, essentially releasing the short forms of both proteins to perform their functions. Whereas the function of OPA1-S

is clearly fusion of the mitochondrial outer membrane, the precise role of PINK1-S remains to be determined. One possibility is that PINK1 (Weihofen et al., 2009), which, like MFN2 (Misko et al., 2010), interacts with the mitochondria-kinesin adaptors Miro and Milton, and with mitofilin (Weihofen et al., 2009), another mitochondrial morphology-related protein (John et al., 2005), assists in the offloading of mitochondria from microtubules in order to allow them to fragment and become autophagized (Gomes et al., 2011 and Hailey et al., 2010). However, the lion’s share of attention to PINK1 CHIR-99021 concentration is devoted to its relationship with Parkin in cooperating in a signaling pathway (Clark et al., 2006) to maintain mitochondrial integrity, presumably by eliminating bad mitochondria via mitophagy (Vives-Bauza

and Przedborski, 2011). As such, we deem the elucidation of the biology of Parkin and PINK1 to be far more important in illustrating the mitochondrial connection to neurodegenerative disease than the few number of patients harboring mutations in these proteins might warrant. In the current view, upon loss of Δψ in damaged mitochondria, PINK1 residing Cyclin-dependent kinase 3 in the outer membrane triggers, in some unknown fashion, the recruitment of cytosolic Parkin to the mitochondria (Jin et al., 2010, Narendra et al., 2010b and Vives-Bauza et al., 2010). Mitochondrial proteins located in the outer membrane, such as the voltage-dependent anion channel 1 (VDAC1; also called porin) are then ubiquitinated

in a Parkin-dependent manner (Geisler et al., 2010). The ubiquitination of outer membrane proteins recruits the autophagy molecule microtubule-associated protein-1 light chain-3 (LC3) to build the autophagosome around the damaged mitochondrion (Vives-Bauza and Przedborski, 2011), apparently mediated by the adaptor proteins HDAC6 (Okatsu et al., 2010) and p62 (Geisler et al., 2010, Narendra et al., 2010a and Okatsu et al., 2010). Upon membrane depolarization, according to some studies, Parkin also induces ubiquitination of mitofusins (Gegg et al., 2010 and Ziviani et al., 2010), which are then degraded by the proteasome via VCP (Tanaka et al., 2010), although others found that it is DRP1 and not MNF1/2 or FIS1 that is degraded by the proteasome in a Parkin-dependent manner (Wang et al., 2011).