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. 2020 Apr 27;29(9):1547–1567. doi: 10.1093/hmg/ddaa077

Figure 8.

Figure 8

Model of OMA1 activation because of loss of C2/C10 and mutant C10. (A) WT C2/C10 are required in a narrow range of expression to prevent L-OPA1 processing by the stress-induced peptidase OMA1. Too low or too high expression of WT C2 or C10 activates OMA1. Activated OMA1 disrupts mitochondrial cristae by cleaving L-OPA1. Some C10 mutations such as G58R appear to lower the threshold concentration for activation of OMA1 by C10. (B) Aggregation-prone mutants of C2 or C10, such as C10 S59L, may activate OMA1 by a different mechanism. Aggregation-prone C10 S59L may co-aggregate with soluble C2 and C10, pulling them into an insoluble fraction. In this setting, OMA1 may be activated by decreased soluble C2/C10, thereby mimicking C2/C10 DKO in a dominant negative mechanism. Alternatively (or in addition), increased insoluble C2/C10 may activate OMA1 by a toxic gain-of-function mechanism.