| Description |
Mitochondria fulfill essential roles in a variety of cellular processes, including ATP generation, Fe-S cluster biogenesis, amino acid metabolism, lipid metabolism, and various signaling pathways. Consistent with their contributions to various processes, mitochondrial dysfunction leads to a wide range of diseases and disorders, including diabetes, neurodegenerative disorders, heart failure, and cancer. To protect cells from mitochondrial dysfunction and subsequent disease, cells have developed a network of pathways responsible for maintaining mitochondrial quality. One of these pathways depends on the Vms1-Cdc48 protein complex. This complex localizes diffusely throughout the cytosol under unstressed conditions, but translocates to mitochondria in response to stress and aids in the degradation of mitochondrial proteins. Using Saccharomyces cerevisiae, we have determined how this stress-responsive localization to mitochondria is regulated. Mitochondrial targeting of Vms1 is mediated by a conserved Mitochondrial Targeting Domain (Vms1MTD), which is inhibited by intramolecular interactions with a N-terminal Leucine Rich Sequence (Vms1LRS) under unstressed conditions. In response to oxidative stress, Vms1LRS inhibition of the Vms1MTD is relieved and Vms1 localizes to damaged mitochondria. Using a combination of genetics, biochemistry, and molecular biology, we determined that ergosterol peroxide (EP) is the receptor to which Vms1 localizes. EP is formed from the nonenzymatic oxidation of ergosterol by reactive oxygen, specifically singlet oxygen. The same stress conditions that promote Vms1 localization to mitochondria induce the accumulation of mitochondrial EP. This leads us to hypothesize that EP levels manifest the degree of stress within a mitochondrion. Furthermore, we suggest that accumulation of EP contributes to disrupting the inhibitory interaction between the Vms1MTD and Vms1LRS, enabling Vms1 to be preferentially recruited to damaged mitochondria. We have also demonstrated that sphingolipids are required for efficient Vms1 translocation to mitochondria. However, we were unable to identify a physiologically relevant sphingolipid species to which Vms1 binds directly. Rather, we hypothesize that sphingolipids are necessary to create lipid microdomains, which help stabilize sterols, such as ergosterol peroxide, in the outer mitochondrial membrane. Taken together, the studies described herein illustrate novel coordination between lipid signaling and mitochondrial quality control pathways. |
