, 2011), for subsequent clearance by the proteasome. This process constitutes, as it were, a mitochondrial

version of ER-associated degradation ( Heo et al., 2010). Interestingly, mutations in VCP were recently selleck found to cause familial ALS ( Johnson et al., 2010). Thus, mutations in mitochondrial quality control genes could prevent the efficient elimination of damaged mitochondria and the degradation of superfluous and potentially deleterious polypeptides, hence leading to neuronal dysfunction and perhaps ultimately to cell death. In order for quality control to operate at the level of the mitochondrion, cells must be able to distinguish between “good” and “bad” organelles, and in fact, such discrimination does occur. Mitochondria apparently are deemed to be good if they have a high membrane potential (Δψ), and perhaps low levels of reactive oxygen species (ROS) as well, both presumably indicative of a well-functioning respiratory chain. Conversely, they are deemed bad if they have a low Δψ and elevated ROS, indicative of defective OxPhos; these are the organelles that are eliminated

via selective mitophagy (Twig and Shirihai, 2011). Mitophagy of damaged organelles, however, is a last resort, as cells initially try to prevent the accumulation Ku-0059436 mouse of bad mitochondria via maintenance of a dynamic equilibrium between mitochondrial fission and fusion, which “homogenizes” organellar contents. This mixing of a few bad mitochondria within a larger pool of good ones allows for complementation of genes and gene products to take place after mitochondria

Linifanib (ABT-869) have exchanged contents (Gilkerson et al., 2008), thereby blunting, or even eliminating, the deleterious effects of misfolded proteins and randomly mutated mtDNAs (Twig and Shirihai, 2011). Thus, from a quality control standpoint, one might predict that mutations in genes encoding proteins required for mitochondrial dynamics, and especially organellar fission and fusion, would result in compromised organellar “mixing,” leading to an excess accumulation of bad mitochondria, perhaps causing disease, and this is indeed the case. Gene products in this category include four associated with fusion (although interestingly, none with fission): MFN2 and GDAP1, both causing CMT, and OA proteins OPA1 and OPA3, both causing OA. Even though OPA1 and OPA3 (Huizing et al., 2010 and Ryu et al., 2010) and GDAP1 (Niemann et al., 2005) interact with mitofusins to regulate the mitochondrial network, it is again worth noting that the four genes are associated with two totally different clinical presentations. Mitochondrial dynamics are also altered in HD (Bossy-Wetzel et al., 2008, Kim et al., 2010 and Oliveira, 2010), as the expression of mitochondrial fission-related proteins, such as FIS1 and DRP1 (Costa et al., 2010), which happens to interact with HTT (Song et al.