Stomatin-like protein 2 senses oxidative stress through the interaction with phosphatidic acid to promote mitochondrial unfolded protein response

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.