Stomatin-like protein 2 senses oxidative stress through the interaction with phosphatidic acid to promote mitochondrial unfolded protein response
Rueda, M. P. C.; Pichler, I.; Musilova, K.; Kmoch, S.; Pramstaller, P. P.; Hnizda, A.; Hicks, A. A.; Vozdek, R.
10.1101/2024.04.30.591949 bioRxivShow abstract
The mitochondrial unfolded protein response (mtUPR) is an essential mechanism that maintains mitochondrial fitness during stress. Using a genetic screen in Caenorhabditis elegans looking for regulators of the mtUPR, we identified stl-1, an ortholog of human Stomatin-like protein 2 (SLP-2), as a positive regulator in healthy mitochondria. The loss of STL-1 and SLP-2 results in an impaired mtUPR in C. elegans and human cells, respectively. Both C. elegans STL-1 and human SLP-2 are proteins located at the inner mitochondrial membrane and exhibit strong lipid binding affinity to phosphatidic acid. Oxidative stress alters the STL-1 localization within the mitochondrial membrane, and triggers the mtUPR dependent on both STL-1/SLP-2 and mitochondrial PA homeostasis. These results reveal an evolutionarily conserved mechanism of mitochondrial protection, in which STL-1/SLP-2 acts as a sensor for changes in mitochondrial membrane lipid composition through physical interaction with PA species, thereby mediating the mtUPR and enhancing stress resistance.
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