FIGURE 7.

Mutant SOD1 binds to VDAC1 and inhibits VDAC1 activities, with addition of a VDAC1 N-terminal peptide preventing such inhibition. Schematic model showing mutant SOD1 binding to VDAC1, with the N-terminal peptide serving as a decoy. (A) Mutant SOD1 is proposed to bind to the VDAC1 N-terminal domain and inhibit VDAC1 conductance, thereby suppressing both influx and efflux of different mitochondrial metabolites and ions, including Ca²⁺, and ROS. This reduction in metabolite flux results in reduced energy production and increased oxidative stress, leading to mitochondrial dysfunction and cell death. (B) VDAC1 N-terminal-derived peptides bind mutant SOD1 and prevent its association with VDAC1, thereby preventing mitochondria dysfunction. The N-terminal peptide thus provides a new therapeutic approach for inhibiting mutant SOD1 toxicity in ALS. OMM and IMM indicate outer and inner mitochondrial membrane, respectively while IMS indicates, the intermembrane space.