Mitochondrial Quality Control Governed by Ubiquitin

Abstract

Mitochondria are essential organelles important for energy production, proliferation, and cell death. Biogenesis, homeostasis, and degradation of this organelle are tightly controlled to match cellular needs and counteract chronic stress conditions. Despite providing their own DNA, the vast majority of mitochondrial proteins are encoded in the nucleus, synthesized by cytosolic ribosomes, and subsequently imported into different mitochondrial compartments. The integrity of the mitochondrial proteome is permanently challenged by defects in folding, transport, and turnover of mitochondrial proteins. Therefore, damaged proteins are constantly sequestered from the outer mitochondrial membrane and targeted for proteasomal degradation in the cytosol via mitochondrial-associated degradation (MAD). Recent studies identified specialized quality control mechanisms important to decrease mislocalized proteins, which affect the mitochondrial import machinery. Interestingly, central factors of these ubiquitindependent pathways are shared with the ER-associated degradation (ERAD) machinery, indicating close collaboration between both tubular organelles. Here, we summarize recently described cellular stress response mechanisms, which are triggered by defects in mitochondrial protein import and quality control. Moreover, we discuss how ubiquitindependent degradation is integrated with cytosolic stress responses, particularly focused on the crosstalk between MAD and ERAD.

The proteasome: friend and foe of mitochondrial biogenesis

“…There is no doubt that the mitochondrial quality control system is crucial to maintain mitochondrial proteostasis and for the dynamic adaptation of the mitochondrial proteome to changing metabolic conditions [9][10][11][12]. Nevertheless, studies over the past decade have shown that the ubiquitin-proteasome system (UPS) of the cytosol is of pivotal relevance for the surveillance of the mitochondrial proteome [13][14][15][16][17]. Particularly important in this context are the degradation of cytosolic mitochondrial precursor proteins and that of mitochondrial surface proteins, the so-called mitochondria-associated degradation (MAD), by the proteasome.…”

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

“…The two main proteolytic pathways of the PQC network, the autophagy-lysosomal system and the UPS, can also impact genome integrity. Not only do they mitigate oxidative DNA damage by controlling mitochondrial quality (Pickles, Vigié, and Youle 2018;Ravanelli et al 2020), they also influence the dynamics of genome maintenance by controlling the turnover of many key DNA repair proteins (Brinkmann et al 2015;Guo and Zhao 2020 ) and the DNA replication machinery (Roseaulin et al 2013;Walter et al 2016). Autophagy also appears to play a key role in maintaining nuclear homeostasis by selectively degrading other nuclear components (i.e.…”

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

“…By serving as a cell death gatekeeper, mitochondria play a central role in cellular quality control and survival decisions. Here, formation of the mitochondrial permeability transition pore and ERAD, Cdc48/p97 and the proteasome assist mitochondrial-associated degradation (MAD) [29,[64][65][66][67] ( Figure 1). Figure 1.…”

“…Consequently, mitochondrial integrity relies on protein import. In addition, mitochondrial homeostasis is maintained by a set of quality control machineries, namely internal proteases, chaperones, and the ubiquitin proteasome system (UPS) [ 27 , 28 , 29 , 30 ]. The UPS is mostly prevalent for proteins resident in the OMM, but also impacts others, e.g., during their import into mitochondria.…”

“…One of the most extensively studied Cdc48/p97 dependent-pathway is the endoplasmatic reticulum-associated degradation (ERAD), where the AAA-ATPase extracts ubiquitylated proteins from the organellar membrane and facilitates their degradation by the proteasome [ 59 , 60 , 61 , 62 , 63 ]. In analogy to its role in ERAD, Cdc48/p97 and the proteasome assist mitochondrial-associated degradation (MAD) [ 29 , 64 , 65 , 66 , 67 ] ( Figure 1 ).…”