RT Journal Article
SR Electronic
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.
FD Society for Neuroscience
SP 11588
OP 11598
DO 10.1523/JNEUROSCI.5385-12.2013
VO 33
IS 28
A1 Tan, Wenzhi (谭文之)
A1 Naniche, Nicole
A1 Bogush, Alexey
A1 Pedrini, Steve
A1 Trotti, Davide
A1 Pasinelli, Piera
YR 2013
UL http://www.jneurosci.org/content/33/28/11588.abstract
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.