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

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.

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

“…Moreover, substrates of the MIA pathway in yeast were found to be ubiquitinated and accumulated in response to proteasome inhibition, even in the presence of active import machinery (Bragoszewski et al , ; Kowalski et al , ). Thus, the proteasome system acts as a vital checkpoint for the improper localization of proteins and promotes efficient mitochondrial IMS protein biogenesis (Bragoszewski et al , , ). The present data demonstrate that mislocalized COA7 is more prone to degradation.…”

Mitochondrial quality control in cardiac cells: Mechanisms and role in cardiac cell injury and disease

“…In this regard, Parkin‐mediated degradation of mitochondrial proteins via proteasomal activation has been reported in several research studies (Chan et al, ; Yoshii, Kishi, Ishihara, & Mizushima, ). Upon changes in mitochondrial membrane potential, Parkin translocates to mitochondria, ubiquitinates mitochondrial outer membrane proteins (Bragoszewski et al, ; D. Narendra, Tanaka, Suen, & Youle, ), and by recruiting proteasome components to mitochondria activates UPS (Chan et al, ; Hammerling & Gustafsson, ). On the other hand, Parkin suppression resulted in the accumulation of Drp1 and mitochondrial fragmentation (Wang et al, ).…”

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

“…Neurodegenerative diseases often display proteasomal defects due to accumulation of neurotoxic molecules such as alpha-synuclein, beta-amyloid or mutant huntingtin that can act as inhibitors of proteasome activity or by overwhelming proteasome activity [32]. Proteasomal involvement in regulation of mitochondrial function is also demonstrated by a number of proteasome components and ubiquitin E3 ligases that associate on the surface of the OMM, such IBRDC2, FBXW7, FBXO7, RFN185 in humans and Rsp5 and Dma1 in budding yeast (see references in [33]. Ubiquitylation of OMM proteins that expose domains and loops to the cytosol can result in one of two outcomes.…”