, 2011), leading to the features of the disease (Schon and Area-Gomez, 2010). One other neurodegenerative disease that may be associated with MAM dysfunction is CMT, which can be caused by mutations both in MFN2 (Chen and Chan, 2009) and in ganglioside-induced
selleck chemicals llc differentiation-associated protein 1 (GDAP1) (Pedrola et al., 2005), which interacts with MFN2 (Niemann et al., 2005). MFN2, like mitofusin-1 (MFN1), is required for mitochondrial fusion (Chen and Chan, 2009). However, a portion of MFN2 is enriched in the MAM, where it is required for the tethering of ER to mitochondria (de Brito and Scorrano, 2008). We note that CMT mutant MFN2 expressed in cultured dorsal root ganglion neurons induced abnormal clustering of fragmented mitochondria, as well as impaired axonal transport of mitochondria (Baloh et al., 2007). Perhaps these abnormalities resulted from an underlying defect in ER-mitochondrial communication. The study of MAM is a nascent field that has just begun to be recognized as a contributor to neurodegeneration, and likely will expand beyond the diseases cited above. For example, there may be a “MAM connection” in at least two other diseases in which the relevant proteins—both involved in phospholipid metabolism—appear to be enriched
in the MAM. These are SCA due to mutations in PPP2R2B, a regulatory subunit of protein phosphatase 2A (Giorgi et al., 2010) that promotes mitochondrial fission (Dagda et al., 2008a), presumably via MAM-localized Paclitaxel clinical trial FIS1 (Iwasawa et al., 2011), and PD due to mutations in subunit β of the calcium-independent phospholipase A2 (iPLA2β; gene
PLA2G6), which plays a key role in ER-mitochondrial all crosstalk during ER stress-induced apoptosis ( Lei et al., 2008). It would thus be fascinating to see if future studies on PPP2R2B and iPLA2β provide insight into a potential link between MAM and neurodegeneration in SCA and PD, and perhaps even beyond. Besides alterations in trafficking and in ER-mitochondrial communication, mitochondria can also fail to reach their destinations due to dysregulation of quality control systems. The cell has surveillance mechanisms to eliminate mutated, unfolded, and otherwise unwanted proteins, via autophagic and ubiquitin-proteasome systems located in the cytosol. In a similar manner, unwanted mitochondria can be disposed of, and their contents recycled, by mitophagy. Although there is currently no evidence that mitochondria contain proteasomes, they do have mechanisms to eliminate misfolded or unneeded polypeptides, via, for example, the AAA (ATPase associated with diverse cellular activities) protease paraplegin/SPG7 and the paraplegin-related protease AFG3L2, and their regulators, the prohibitins PHB and PHB2 ( Osman et al., 2009).
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