RT Journal Article
SR Electronic
T1 Discovery of bactericides as an acute mitochondrial membrane damage inducer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.09.439218
DO 10.1101/2021.04.09.439218
A1 Ryan Houston
A1 Yusuke Sekine
A1 Mads B Larsen
A1 Kei Murakami
A1 Derek P Narendra
A1 Bill B Chen
A1 Shiori Sekine
YR 2021
UL http://biorxiv.org/content/early/2021/04/11/2021.04.09.439218.abstract
AB Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The defined lipid composition and structure of mitochondrial membranes are critical for the proper functioning of mitochondria. However, mitochondrial stress responses that help maintain the integrity of mitochondrial membranes against internal or external insults are not well understood. One reason for this lack of insight is the absence of efficient tools to specifically damage mitochondrial membranes. Here, through a compound screen originally aimed at identifying inhibitors of the inner mitochondrial membrane (IMM)-resident protease OMA1, we found that two bis-biguanide compounds, Chlorhexidine and Alexidine, modified OMA1 activity by altering the integrity of the IMM. Interestingly, these compounds are well-known bactericides whose mechanism of action has centered on their damage-inducing activity on bacterial membranes. We found Alexidine binds to the IMM likely through the electrostatic interaction driven by the membrane potential as well as an affinity for anionic phospholipids. Electron microscopic analysis revealed that Alexidine severely perturbated the IMM, especially the cristae structure. Along with this, we observed the altered localization of IMM-resident membrane-shaping proteins, including Mic60. Notably, Alexidine evoked a specific transcriptional/proteostasis signature that was not induced by other typical mitochondrial stressors, highlighting the unique property of Alexidine as a novel mitochondrial membrane stressor. Our findings provide a chemical-biological tool that can induce acute and selective perturbation of the IMM integrity, which should enable the delineation of mitochondrial stress-signaling pathways required to maintain the mitochondrial membrane homeostasis.Competing Interest StatementThe authors have declared no competing interest.