Ubiquitination of specific mitochondrial matrix proteins

Lehmann, Gilad; Ziv, Tamar; Braten, Ori; Admon, Arie; Udasin, Ronald G.; Ciechanover, Aaron

doi:10.1016/j.bbrc.2016.04.150

Cited by 33 publications

(27 citation statements)

References 29 publications

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“…The import of ubiquitinated precursor proteins could provide an explanation for ubiquitin-conjugated internal mitochondrial proteins. A recent report described a case of ubiquitination in the mitochondrial matrix, thus opening a new area of study [61]. The internal features of mitochondrial proteins that are required for their specific recognition by the UPS are also unknown.…”

Section: Discussionmentioning

confidence: 99%

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

2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

2017

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“…Whilst some of the mitochondrial proteins are ultimately matrix associated, they are synthesised in the cytosol and imported through the TIM/TOM complex providing the opportunity to encounter cytosolic Parkin. Interestingly, the presence of ubiquitinated proteins within the yeast mitochondrial matrix has recently been reported [72]. In fact, a recent paper suggested that Parkin ubiquitinates and regulates the stability of the mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) [73].…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons

Amador

Lectez

Ramírez

et al. 2017

Mol Neurodegeneration

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BackgroundParkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson’s Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings.MethodsHere we utilized the recently introduced BioUb strategy to isolate ubiquitinated proteins in flies. Following Parkin Wild-Type (WT) and Parkin Ligase dead (LD) expression we analysed by mass spectrometry and stringent bioinformatics analysis those proteins differentially ubiquitinated to provide the first survey of steady state Parkin substrates using an in vivo model. We further used an in vivo ubiquitination assay to validate one of those substrates in SH-SY5Y cells.ResultsWe identified 35 proteins that are more prominently ubiquitinated following Parkin over-expression. These include several mitochondrial proteins and a number of endosomal trafficking regulators such as v-ATPase sub-units, Syx5/STX5, ALiX/PDCD6IP and Vps4. We also identified the retromer component, Vps35, another PD-associated gene that has recently been shown to interact genetically with parkin. Importantly, we validated Parkin-dependent ubiquitination of VPS35 in human neuroblastoma cells.ConclusionsCollectively our results provide new leads to the possible physiological functions of Parkin activity that are not overtly biased by acute mitochondrial depolarisation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0170-3) contains supplementary material, which is available to authorized users.

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“…The mitochondrial import and clearance of cytosolic proteins was in particular observed on acute heat shock and inhibition of cytosolic Hsp70, suggesting that this pathway functions to buffer extensive cytosolic proteotoxic stress (Ruan et al, 2017). The presence of ubiquitinated proteins inside mitochondria was suggested, which could perhaps result from similar surveillances principles (Lehmann et al, 2016). However, this does not necessarily imply a functional role of ubiquitin inside mitochondria.…”

Section: Mitochondrial Contributions To Mitigate Aggregation Toxicitymentioning

confidence: 99%

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

Escobar-Henriques¹,

Altin²,

Brave³

2020

Current Issues in Molecular Biology

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Eukaryotic cells are subdivided into membranebound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartmentspecific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.

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Ubiquitination of specific mitochondrial matrix proteins

Cited by 33 publications

References 29 publications

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

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

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

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