Abstract
SummaryThiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2 sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis.
Highlights
Disulfide bond formation is crucial for the native structure and stability of many proteins, while redox regulation through reversible cysteine oxidation is a common cellular strategy to adapt protein function to redox conditions
Our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis
We examined whether loss of GPX3 abrogates the mitochondrial membrane potential in mitochondria isolated from wild-type and gpx3 mutant strains by evaluating the incorporation of the fluorescent dye 3,30-dipropylthiadicarbocyanine iodide (DiSC3(5)) in mitochondria with active membrane potential (Figure 3B)
Summary
Disulfide bond formation is crucial for the native structure and stability of many proteins, while redox regulation through reversible cysteine oxidation is a common cellular strategy to adapt protein function to redox conditions. Oxidative stress may have detrimental effects on cell physiology through thiol oxidation, which is why cells have evolved several enzymatic mechanisms to cope with such conditions These include the glutaredoxin and thioredoxin systems, which are the major cellular protein disulfide reduction systems (Morano et al, 2012). Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) that can lead to oxidative damage but can act as a signaling molecule (Veal and Day, 2011) It is normally produced within cells from the dismutation of superoxide anions, as a product of NADPH oxidases, or as a byproduct of the mitochondrial respiratory chain (Murphy, 2009). The active form of Yap is generated by the formation of intramolecular disulfide bridges within Yap1 In this manner, Gpx functions as a H2O2 transducer in the cytosol (Toledano et al, 2004)
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