Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis

Abstract

Small Heat Shock Protein Family B (HSPB) members are ATP-independent chaperones essential for maintaining cellular proteostasis. Together with chaperones and co-chaperones such as HSP70 and BAG3, they prevent aberrant protein folding and suppress protein aggregation, particularly under proteotoxic stress. HSPBs have also been extensively linked to neurodegenerative disease and in promoting chemoresistance in cancer. We previously showed that members of the HSPB family can reside within the mitochondrial intermembrane space where they contribute to the maintenance of proteostasis, and that acute cytotoxic stress leads to HSPB sequestration to the outer mitochondrial membrane. Here, we further elucidate this mechanism, demonstrating that HSPB1 is selectively enriched within mitochondria under milder thermal stress condition, exhibiting a pronounced association with the outer mitochondrial membrane. We also observed distinct stress-dependent mitochondrial recruitment profiles across HSPB paralogs, revealing a similar behaviour for HSPB8, whereby HSPB1 responded at a comparatively lower stress threshold, indicating functional specialization within the HSPB family. Inducing this mechanism enhances cell survival during hyperthermic stress, preventing Cytochrome c release, and raising the apoptotic activation threshold in our experimental system. These findings indicate that HSPBs, particularly HSPB1 may contribute to mitochondrial stress adaptation prior to Cytochrome c release. This underexplored mechanism may underlie the modulation of stress-related and degenerative disease progression and contribute to the chemoresistance associated with cancer, which have been attributed to HSPBs.