Mitochondria communicate with other cellular compartments via the secretion of protein factors. Here, we report an unexpected messenger role for heat shock protein 60 (HSP60) as a mitochondrial-releasing protein factor that couples stress-sensing signaling and cell survival machineries. We show that mild oxidative stress predominantly activates the p38/MK2 complex, which phosphorylates mitochondrial fission factor 1 (MFF1) at the S155 site. Such phosphorylated MFF1 leads to the oligomerization of voltage anion-selective channel 1, thereby triggering the formation of a mitochondrial membrane pore through which the matrix protein HSP60 passes. The liberated HSP60 associates with and activates the IκB kinase (IKK) complex in the cytosol, which consequently induces the NF-κB-dependent expression of survival genes in nucleus. Indeed, inhibition of the HSP60 release or HSP60-IKK interaction sensitizes the cancer cells to mild oxidative stress and regresses the tumorigenic growth of cancer cells in the mouse xenograft model. Thus, this study reveals a novel mitonuclear survival axis responding to oxidative stress.
Bibliographical noteFunding Information:
We thank Drs. Tamas Balla and Bert Vogelstein for live-cell imaging vectors and HCT116 cell lines, respectively. This study was supported by grants from the National Research Foundation of Korea ( 2018R1A2B3006323 and 2017M3A9B6073098 ). C.M. was also supported by grants from the National Research Foundation of Korea ( 2019R1I1A1A01057557 ) and the RP- Grant ( 2018 - 2019 ) of Ewha Womans University .
© 2022 The Authors
- Oxidative stress
- p38 MAPK
ASJC Scopus subject areas
- Organic Chemistry