TY - JOUR T1 - Small Peptides against the Mutant SOD1/Bcl-2 Toxic Mitochondrial Complex Restore Mitochondrial Function and Cell Viability in Mutant SOD1-Mediated ALS JF - The Journal of Neuroscience JO - J. Neurosci. SP - 11588 LP - 11598 DO - 10.1523/JNEUROSCI.5385-12.2013 VL - 33 IS - 28 AU - Tan, Wenzhi (谭文之) AU - Nicole Naniche AU - Alexey Bogush AU - Steve Pedrini AU - Davide Trotti AU - Piera Pasinelli Y1 - 2013/07/10 UR - http://www.jneurosci.org/content/33/28/11588.abstract N2 - Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS) in 20% of familial cases (fALS). Mitochondria are one of the targets of mutant SOD1 (mutSOD1) toxicity. We previously demonstrated that at the mitochondria, mutSOD1 forms a toxic complex with Bcl-2, which is then converted into a toxic protein via a structural rearrangement that exposes its toxic BH3 domain (Pedrini et al., 2010). Here we now show that formation of this toxic complex with Bcl-2 is the primary event in mutSOD1-induced mitochondrial dysfunction, inhibiting mitochondrial permeability to ADP and inducing mitochondrial hyperpolarization. In mutSOD1-G93A cells and mice, the newly exposed BH3 domain in Bcl-2 alters the normal interaction between Bcl-2 and VDAC1 thus reducing permeability of the outer mitochondrial membrane. In motor neuronal cells, the mutSOD1/Bcl-2 complex causes mitochondrial hyperpolarization leading to cell loss. Small SOD1-like therapeutic peptides that specifically block formation of the mutSOD1/Bcl-2 complex, recover both aspects of mitochondrial dysfunction: they prevent mitochondrial hyperpolarization and cell loss as well as restore ADP permeability in mitochondria of symptomatic mutSOD1-G93A mice. ER -