Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria

• Published in: Molecular cell Vol. 68; no. 4; pp. 673 - 685.e6
• Main Authors: Nielson, Jason R., Fredrickson, Eric K., Waller, T. Cameron, Rendón, Olga Zurita, Schubert, Heidi L., Lin, Zhenjian, Hill, Christopher P., Rutter, Jared
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-11-2017; Elsevier
• Subjects: biochemistry; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Crystallography, X-Ray; Ergosterol - analogs & derivatives; Ergosterol - metabolism; lipid signaling; liposomes; Mitochondria - chemistry; Mitochondria - genetics; Mitochondria - metabolism; mitochondrial quality control; Oxidation-Reduction; oxidative stress; protein degradation; Protein Domains; Protein Transport; ROS signaling; S. cerevisiae; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; sterols; structure-function; mitochondrial quality control; liposomes; S. cerevisiae; ROS signaling; biochemistry; structure-function; sterols; lipid signaling; oxidative stress; protein degradation
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2017.10.022

Vms1 translocates to damaged mitochondria in response to stress, whereupon its binding partner, Cdc48, contributes to mitochondrial protein homeostasis. Mitochondrial targeting of Vms1 is mediated by its conserved mitochondrial targeting domain (MTD), which, in unstressed conditions, is inhibited by intramolecular binding to the Vms1 leucine-rich sequence (LRS). Here, we report a 2.7 Å crystal structure of Vms1 that reveals that the LRS lies in a hydrophobic groove in the autoinhibited MTD. We also demonstrate that the oxidized sterol, ergosterol peroxide, is necessary and sufficient for Vms1 localization to mitochondria, through binding the MTD in an interaction that is competitive with binding to the LRS. These data support a model in which stressed mitochondria generate an oxidized sterol receptor that recruits Vms1 to support mitochondrial protein homeostasis.
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•Stress induces Vms1 mitochondrial localization independently of protein interaction•Ergosterol peroxide (EP) binding mediates Vms1 mitochondrial localization•The Vms1 leucine-rich sequence (LRS) binds the mitochondrial targeting domain (MTD)•The LRS competes with EP for MTD binding to inhibit Vms1 mitochondrial localization
Vms1 translocates to damaged mitochondria in response to stress by unknown mechanisms. Here, Nielson et al. demonstrate that Vms1 mitochondrial translocation is regulated by a hydrophobic intramolecular interaction and the accumulation of an oxidized sterol, ergosterol peroxide. This study implicates sterol oxidation as a mechanism for mitochondrial stress response.