Two Ways to Redox Regulation: Eukaryotic cells control the redox environment within their cytoplasm to be generally reducing. However, the endoplasmic reticulum provides an oxidizing environment for secretory and membrane proteins. In addition, a subcompartment of mitochondria—the powerhouses of the cell—also generates an oxidizing environment for constituent and itinerant proteins. Riemer et al. (p. 1284 ) review the current understanding of both eukaryotic redox machineries and highlight their implications for the biogenesis and regulation of protein function, focusing on the impact of these systems on health and disease.

All proteins of the intermembrane space of mitochondria are encoded by nuclear genes and synthesized in the cytosol. Many of these proteins lack presequences but are imported into mitochondria in an oxidation-driven process that relies on the activity of Mia40 and Erv1. Both factors form a disulfide relay system in which Mia40 functions as a receptor that transiently interacts with incoming polypeptides via disulfide bonds. Erv1 is a sulfhydryl oxidase that oxidizes and activates Mia40, but it has remained unclear how Erv1 itself is oxidized. Here, we show that Erv1 passes its electrons on to molecular oxygen via interaction with cytochrome c and cytochrome c oxidase. This connection to the respiratory chain increases the efficient oxidation of the relay system in mitochondria and prevents the formation of toxic hydrogen peroxide. Thus, analogous to the system in the bacterial periplasm, the disulfide relay in the intermembrane space is connected to the electron transport chain of the inner membrane.

The biogenesis of mitochondria depends on the import of hundreds of preproteins. N-terminal matrix-targeting signals (MTSs) direct preproteins to the surface receptors Tom20, Tom22, and Tom70. In this study, we show that many preproteins contain additional internal MTS-like signals (iMTS-Ls) in their mature region that share the characteristic properties of presequences. These features allow the in silico prediction of iMTS-Ls. Using Atp1 as model substrate, we show that iMTS-Ls mediate the binding to Tom70 and have the potential to target the protein to mitochondria if they are presented at its N terminus. The import of preproteins with high iMTS-L content is significantly impaired in the absence of Tom70, whereas preproteins with low iMTS-L scores are less dependent on Tom70. We propose a stepping stone model according to which the Tom70-mediated interaction with internal binding sites improves the import competence of preproteins and increases the efficiency of their translocation into the mitochondrial matrix.

ER-SURF protein import into mitochondria: Eukaryotic cells contain membrane-bound organelles, defined by distinct protein compositions. Almost all cellular proteins are synthesized in the cytosol, and thus, organelle-resident proteins must be directed to their appropriate location after synthesis. Working in yeast, Hansen et al. identified a protein-targeting paradigm termed ER-SURF, in which the membrane expanse of the endoplasmic reticulum (ER) serves as a “capture net” for mitochondrial proteins. This process productively redirected mitochondrial precursor proteins for efficient mitochondrial import. Thus, two distinct organelles, once thought to be mutually exclusive protein destinations, can cooperate during protein targeting. Science , this issue p. 1118