Stomatin-like protein 2 senses oxidative stress through the interaction with phosphatidic acid to promote mitochondrial unfolded protein response
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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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A regulatory role for mitochondrial PA through SLP-2 thus provides new possibilities of therapeutic targeting for diseases with mitochondrial involvement.
LPA signaling has been implicated in promoting mitochondrial homeostasis as well as promoting mitochondrial apoptosis in pathologic conditions. Since STL-1 can bind LPA, I’m wondering if you can comment on how extra and intra-cellular LPA signaling may impact STL-1 function?
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Nonetheless, further studies are needed to delineate the exact mechanism of PA-mediated regulation of STL-1/SLP-2
It will be interesting to model how pH changes can change STL-1-lipid interactions and generate point mutations to disrupt binding and observe outcomes.
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Interestingly, using animals carrying zcIs13(hsp-6p::GFP), another established reporter of mtUPR activation (17), we observed significantly decreased GFP fluorescence only in the stl-1 mutants with missense mutations R51K and M308I, while the GFP levels in the adult stl-1 null mutants were not significantly altered compared to wild type (WT)
Thanks for posting your great study on linking STL-1 to phosphatidic acid signaling and mtUPR. Can you confirm that tm1544 or other point mutants behave as a true null alleles (e.g. place tm1544 over a larger chromosomal deletion and confirm that tm1544/- phenocopies -/- animals?). Since the hps-6p::GFP reporter behaves differently when crossed with the different stil-1 mutants, is it possible that the mutations are not equivalent and regulate the hsp-6 and hsp-60 reporters differently?
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