Fig. 8. Proposed model of the chaperone-like activity of MIF.

A fraction of mutant SOD1 or wild type SOD1 under stress conditions accumulates as a toxic misfolded protein. This misfolded protein associates with mitochondrial or ER membranes, thereby causing mitochondrial dysfunction or ER stress, respectively, leading to cell death. Alternatively, the misfolded SOD1 proteins may aggregate as toxic amyloid fibrils that cause cell death. By directly interacting with the misfolded SOD1, MIF prevents it from accumulating and associating with intracellular membranes, thereby reducing its toxic effect. In addition, MIF inhibits SOD1 amyloid fibril formation and promotes instead, the formation of less toxic amorphous aggregates.