Description
We have recently shown that wild-type α-syn is not present in mitochondria as previously thought (Li et al., 2007: Cole et al., 2008: Devi et al., 2008: Parihar et al., 2008) but rather is in the MAM (Guardia-Laguarta et al., 2014). Remarkably, we found that PD-related mutated α-syn result in its reduced association with MAM, coincident with a lower degree of apposition of ER with mitochondria, and an increase in mitochondrial fragmentation, as compared to wild-type. This striking fragmentation phenotype could not be rescued by pharmacological or genetic interventions aimed at modulating the molecular machinery that controls mitochondrial shape and size, implying that α-syn operates downstream of it. However, overexpression of wild-type α-syn in mutant α-syn-expressing cells rescued the fragmented phenotype. These novel results indicate that wild-type α-syn localizes to the MAM and modulates mitochondrial morphology, and that these behaviors are impaired by pathogenic mutations in α-syn.
Example of colocalization of ER labeled with GFP-Sec61-Beta (green), and mitochondria labeled with pDsRed2-mito (red), in M17 dopaminergic cell expressing A30P- synculein mutation.