N-terminal α-amino SUMOylation promotes phosphorylation-independent cofilin-1 translocation to the mitochondrial matrix and induces apoptosis.

Abstract

Cofilin is a central regulator of actin filament turnover, traditionally thought to act through phosphorylation-dependent control of filament assembly. However, its mitochondrial functions remain poorly understood. Here we show that N-terminal α-amino SUMOylation, rather than phosphorylation or actin interaction, governs cofilin-1 translocation to mitochondria and activation of the apoptotic pathway. This modification strengthens the association of cofilin-1 with the mitochondrial import receptors Tom20 and Tom70 through the molecular chaperone HSP70, enabling its delivery to the mitochondrial matrix. Once imported, SUMO-modified cofilin-1 binds cytochrome c1, promotes the dissociation of cytochrome c from complex III, and initiates mitochondrial-mediated apoptosis. These findings redefine cofilin-1 as a regulator of mitochondrial integrity independent of its actin-related roles, uncovering a mechanism by which SUMOylation directs protein targeting and apoptotic signaling. This work broadens current understanding of mitochondrial regulation and may inform therapeutic strategies for diseases linked to defective cell death.