Proteasomal degradation competes with Mia40-mediated import into mitochondria

Abstract

Tandem fluorescent protein timers are elegant tools to determine proteolytic stabilities of cytosolic proteins with high spatial and temporal resolution. In a new study published in BMC Biology, Kowalski et al. fused timers to precursors of proteins of the mitochondrial intermembrane space and found that they are under surveillance of the ubiquitin-proteasome system. Ubiquitination at lysine residues of these precursors directly inhibits their translocation into the intermembrane space and targets them for proteasomal degradation.

The NADH Dehydrogenase Nde1 Executes Cell Death after Integrating Signals from Metabolism and Proteostasis on the Mitochondrial Surface

“…We also observed that in whole cell extracts, but not in isolated mitochondria, several Nde1-derived fragments are detected (Figure 5A), suggesting that the cytosol-exposed topomer is preferentially degraded. Several recent studies have identified two major proteolytic systems that control the levels of IMS and outer membrane proteins, namely the Cdc48/proteasome system in the cytosol and the i-AAA protease Yme1 in the IMS (Jin et al, 2010;Kowalski et al, 2018;Leonhard et al, 1996;Må rtensson et al, 2019;Rampello and Glynn, 2017;Steffen et al, 2017;Vö gtle et al, 2011;Wrobel et al, 2015;Wu et al, 2018;Xu et al, 2011;Zö ller et al, 2018). We employed a stability assay in which we monitored cellular Nde1 levels after inhibition of protein synthesis by cycloheximide ( Figure 5B).…”

Disease-Associated Genetic Variation in Human Mitochondrial Protein Import

“…42 The dramatic reduction of CHCHD10 import, also observed upon CHCHD4 knockdown, supports the idea that import of MIA substrates into the IMS competes with their ubiquitin-dependent degradation in the cytosol. 43,44 In two additional examples, rare myopathies are caused by autosomal-recessive inheritance of components of the MIA pathway. In one example, an autosomal-recessive myopathy (MIM: 600924) is associated with an inherited variant in the core component of the MIA pathway ALR (GFER/ERV1).…”

Moschamindole induces glioma cell apoptosis by blocking Mia40‐dependent mitochondrial intermembrane space assembly and oxidative respiration

“…The mitochondrial intermembrane space (IMS) assembly (Mia) pathway is specifically focused on the redox-dependent import and modification of proteins localized to the IMS of mitochondria (Banci et al, 2009;Fraga et al, 2014;Gornicka et al, 2014). The oxidoreductase Mia40 is a crucial component of the pathway responsible for the oxidative folding and transfer of disulphide bonds to precursor proteins that are rich in cysteine residues (Chacinska et al, 2004a;Terziyska et al, 2005;Zoller, Todd Alexander, & Herrmann, 2018).…”

“…Inhibiting Mia40 functionality might result in impaired import or oxidative folding capacity, leading to reduced abundance of its substrates, such as the subunits and assembly factors of oxidative respiration complexes (Zoller et al, 2018). Additionally, Mia40 dysregulation has been demonstrated to contribute to the erroneous assembly of inner membrane complexes, such as electron transport chain (ETC) components, thus destroying the energy production and mitochondrial homeostasis in severe human diseases (Rissler et al, 2005).…”