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Review
. 2017 Apr;7(4):170007.
doi: 10.1098/rsob.170007.

Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system

Piotr Bragoszewski  1 , Michal Turek  2 , Agnieszka Chacinska  3   4
Affiliations
Review

Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system

Piotr Bragoszewski et al. Open Biol. 2017 Apr.

Abstract

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin-proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level.

Keywords: mitochondria; proteasome; protein biogenesis; proteostasis; ubiquitin; ubiquitin–proteasome system.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
Cellular fate of mitochondrial precursor proteins translated in the cytosol. (a) The majority of mitochondrial proteins are encoded by genomic DNA, and their translation is executed outside mitochondria. After synthesis on ribosomes, mitochondrial proteins are transported to their destination inside mitochondria. In the case of failure of any of the processes that are involved in protein synthesis or transportation to the organelle, proteins are ubiquitinated and degraded by the proteasome or can form aggregates in the cytosol. (b) Schematic representation of mitochondrial protein translocation and sorting pathways. Precursor proteins that are synthesized in the cytosol cross the outer mitochondrial membrane by a common entry gate: the translocase of the outer membrane (TOM) complex. They are then routed by sorting pathways to their target location within mitochondria. Proteins that are destined to the outer membrane are built into the membrane by sorting and assembly machinery (SAM) or use the insertase of the mitochondrial outer membrane (MIM). Many proteins of the intermembrane space follow the mitochondrial import and assembly (MIA) pathway. Insertion into the inner mitochondrial membrane is mediated by translocases of the inner membrane TIM22 and TIM23. Matrix proteins use the TIM23 translocase coupled with the presequence translocase-associated motor (PAM).
Figure 2.
Figure 2.
Ubiquitin–proteasome system involvement in the regulation of mitochondrial dynamics. The mitochondrial network in living cells undergoes constant changes that involve organelle fusion and fission (division). Because of the importance of mitochondria, the proper regulation of these processes is critical for cell health. Fusion and fission antagonist processes are regulated by several proteins that promote one or another series of actions. In mammalian cells, during the fission process, Drp1 and Fis1 proteins accumulate on the mitochondrial outer membrane, whereas Mfn1 and Mfn2 proteins are ubiquitinated and degraded by the proteasome. In the process of mitochondrial fusion, the opposite direction is observed, in which Mfn1 and Mfn2 protein levels increase, and Drp1 and Fis1 proteins are directed for proteasomal degradation.
Figure 3.
Figure 3.
Proteasome-dependent strategies of mitochondrial protein degradation. Mitochondrial proteins are exposed to the proteasomal degradation in several ways. (a) The mitochondria-associated protein degradation (MAD) process is homologous to endoplasmic reticulum-associated protein degradation (ERAD). During MAD, mitochondrial outer membrane (OM) proteins are extracted from the organelle through the highly conserved AAA-ATPase Cdc48 (yeast; VCP or p97 in mammals) and directed to proteasomal degradation. (b) The proteasomal degradation of mitochondrial proteins also occurs after protein retro-translocation from the mitochondrial intermembrane space. Once proteins are translocated to the mitochondrion through the TOM complex, they are trapped inside the organelle as a result of their oxidative folding that is orchestrated by the mitochondrial import and assembly (MIA) machinery. If the disulfide bonds are not formed or become reduced, then the protein can retro-translocate and be degraded by the proteasome in the cytosol. (c) The proteasome is also involved in the degradation of mitochondrial precursor proteins that fail to be transported to the organelle because of defects in protein import or protein stalling on the translocase of the outer membrane (TOM) complex.
Figure 4.
Figure 4.
Proteasome activity modulation by reactive oxygen species levels and mitochondrial protein transport impairment. (a) An increase in reactive oxygen species (ROS) levels causes higher proteasome activity. A mild increase in ROS levels promotes stronger activity of the 26S proteasome. High ROS levels promote stronger activity of the 20S proteasome. Finally, after a prolonged increase in ROS, more active, alternative proteasome complexes are formed. (b) Impairment in mitochondrial protein transport leads to the accumulation of mitochondrial precursor proteins in the cytosol. This increases proteasome assembly and activation in the process of unfolded protein response activated by mistargeted proteins (UPRam).
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