The biogenesis of mitochondrial intermembrane space proteins

Abstract

<jats:title>Abstract</jats:title><jats:p>The mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understanding the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness.</jats:p>

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

“…Many proteins of the IMS lack presequences and their import relies on cysteine motives [27]. The oxidoreductase Mia40 (CHCHD4 in humans) and the sulfhydryl oxidase Erv1 (ALR in human) drive the import reaction of these proteins [28,29].…”

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).…”

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

“…Following translocation through the TOM complex, proteins are sorted by several additional complexes in the outer and inner membrane to their respective mitochondrial subcompartment. The mechanisms by which the mitochondrial protein import systems mediates these protein translocation reactions were analyzed in detail over the last three decades and are described in several comprehensive reviews (Chacinska et al, 2009;Endo et al, 2011;Callegari et al, 2020;Drwesh and Rapaport, 2020;Edwards et al, 2020;Mokranjac, 2020;Schneider, 2020).…”

“…, 2011 ; Callegari et al. , 2020 ; Drwesh and Rapaport, 2020 ; Edwards et al. , 2020 ; Mokranjac, 2020 ; Schneider, 2020 ).…”