PT  - JOURNAL ARTICLE
AU  - Tan, Wenzhi (谭文之)
AU  - Naniche, Nicole
AU  - Bogush, Alexey
AU  - Pedrini, Steve
AU  - Trotti, Davide
AU  - Pasinelli, Piera
TI  - Small Peptides against the Mutant SOD1/Bcl-2 Toxic Mitochondrial Complex Restore Mitochondrial Function and Cell Viability in Mutant SOD1-Mediated ALS
AID  - 10.1523/JNEUROSCI.5385-12.2013
DP  - 2013 Jul 10
TA  - The Journal of Neuroscience
PG  - 11588--11598
VI  - 33
IP  - 28
4099  - http://www.jneurosci.org/content/33/28/11588.short
4100  - http://www.jneurosci.org/content/33/28/11588.full
SO  - J. Neurosci.2013 Jul 10; 33
AB  - 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.