Protein import by the mitochondrial disulfide relay in higher eukaryotes

Abstract

<jats:title>Abstract</jats:title><jats:p>The proteome of the mitochondrial intermembrane space (IMS) contains more than 100 proteins, all of which are synthesized on cytosolic ribosomes and consequently need to be imported by dedicated machineries. The mitochondrial disulfide relay is the major import machinery for soluble proteins in the IMS. Its major component, the oxidoreductase MIA40, interacts with incoming substrates, retains them in the IMS, and oxidatively folds them. After this reaction, MIA40 is reoxidized by the sulfhydryl oxidase augmenter of liver regeneration, which couples disulfide formation by this machinery to the activity of the respiratory chain. In this review, we will discuss the import of IMS proteins with a focus on recent findings showing the diversity of disulfide relay substrates, describing the cytosolic control of this import system and highlighting the physiological relevance of the disulfide relay machinery in higher eukaryotes.</jats:p>

The chaperone-binding activity of the mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress

“…Many mitochondrial proteins, however, lack presequences and embark on other import routes into mitochondria. This is the case for all proteins of the outer membrane and most components of the intermembrane space (IMS) that use several distinct pathways (Drwesh and Rapaport, 2020;Wiedemann and Pfanner, 2017;Finger and Riemer, 2020;Edwards et al, 2020;Doan et al, 2020). In addition, many mitochondrial inner membrane proteins, in particular the members of the metabolite carrier family (carriers for short), lack presequences and are imported by a distinct ''carrier pathway'' (Horten et al, 2020;Rehling et al, 2004).…”

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

“…Superoxide generated in the mitochondria can be dismutated to H 2 O 2 by the mitochondrial superoxide dismutases located in the mitochondrial matrix (SOD2) and intermembrane space (SOD1). The enzymes that facilitate disulfide bond formation in the inner membrane space also generate H 2 O 2 as a byproduct [ 69 , 70 ]. In an analogous system to ERO1-PDI pathways, electrons removed during the formation of a disulfide bond in a mitochondrial protein are transferred to the flavoprotein Erv1/ALR via the oxidoreductase Mia40/CHCHD4.…”

Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain

“…Unlike the proteins bound to the mitochondrial membranes or matrix by dedicated import machinery constituting a plethora of proteins, the IMS proteins are brought in and retained in the IMS by a unique pathway called the disulphide relay pathway [ 2 , 3 ]. The import of the IMS targeted proteins is coupled to their folding and oxidation by the disulphide relay pathway [ 4 , 5 ]. MIA40 (Mitochondrial intermembrane space import and assembly protein 40)/CHCHD4 (coiled-coil-helix-coiled-coil-helix-domain containing 4) and ALR (Augmenter of liver regeneration) are the two important known proteins of this pathway [ 2 , 3 ].…”

“…ALR (Erv1 in yeast) recycles reduced MIA40 to its oxidized form to initiate another import cycle. The downstream trail of the electrons from ALR reaches the ETC via cytochrome C [ 3 , 4 ]. The hydrophobic binding cleft of MIA40 recognizes the substrates to introduce the disulphide bonds and to trigger subsequent folding of the precursor proteins.…”