scholarly journals Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria

2017 ◽  
Vol 28 (5) ◽  
pp. 600-612 ◽  
Author(s):  
Janos Steffen ◽  
Ajay A. Vashisht ◽  
Jijun Wan ◽  
Joanna C. Jen ◽  
Steven M. Claypool ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Dynamics ◽  
Outer Membrane Proteins ◽  
Ubiquitin Proteasome System ◽  
Organized Activities ◽  
Pontocerebellar Hypoplasia ◽  
Mitochondrial Carrier ◽  
Rapid Degradation ◽  
Ubiquitin Proteasome ◽  
Mitochondrial Carrier Protein

SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane–associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.

scholarly journals Mitochondrial inner-membrane protease Yme1 degrades outer-membrane proteins Tom22 and Om45

2017 ◽  
Vol 217 (1) ◽  
pp. 139-149 ◽  
Author(s):  
Xi Wu ◽  
Lanlan Li ◽  
Hui Jiang
Keyword(s):  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Outer Membrane ◽  
Intermembrane Space ◽  
Inner Membrane ◽  
Mitochondrial Proteome ◽  
Mitochondrial Inner Membrane ◽  
Ubiquitin Proteasome

Mitochondria are double-membraned organelles playing essential metabolic and signaling functions. The mitochondrial proteome is under surveillance by two proteolysis systems: the ubiquitin–proteasome system degrades mitochondrial outer-membrane (MOM) proteins, and the AAA proteases maintain the proteostasis of intramitochondrial compartments. We previously identified a Doa1–Cdc48-Ufd1-Npl4 complex that retrogradely translocates ubiquitinated MOM proteins to the cytoplasm for degradation. In this study, we report the unexpected identification of MOM proteins whose degradation requires the Yme1-Mgr1-Mgr3 i-AAA protease complex in mitochondrial inner membrane. Through immunoprecipitation and in vivo site-specific photo–cross-linking experiments, we show that both Yme1 adapters Mgr1 and Mgr3 recognize the intermembrane space (IMS) domains of the MOM substrates and facilitate their recruitment to Yme1 for proteolysis. We also provide evidence that the cytoplasmic domain of substrate can be dislocated into IMS by the ATPase activity of Yme1. Our findings indicate a proteolysis pathway monitoring MOM proteins from the IMS side and suggest that the MOM proteome is surveilled by mitochondrial and cytoplasmic quality control machineries in parallel.

scholarly journals Proteostasis and Mitochondrial Role on Psychiatric and Neurodegenerative Disorders: Current Perspectives

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Pablo Olivero ◽  
Carlo Lozano ◽  
Ramón Sotomayor-Zárate ◽  
Nicolás Meza-Concha ◽  
Marcelo Arancibia ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Compensatory Mechanisms ◽  
Mitochondrial Functions ◽  
Ubiquitin Proteasome ◽  
Psychiatric Conditions ◽  
Therapeutic Alternatives

Proteostasis involves processes that are fundamental for neural viability. Thus, protein misfolding and the formation of toxic aggregates at neural level, secondary to dysregulation of the conservative mechanisms of proteostasis, are associated with several neuropsychiatric conditions. It has been observed that impaired mitochondrial function due to a dysregulated proteostasis control system, that is, ubiquitin-proteasome system and chaperones, could also have effects on neurodegenerative disorders. We aimed to critically analyze the available findings regarding the neurobiological implications of proteostasis on the development of neurodegenerative and psychiatric diseases, considering the mitochondrial role. Proteostasis alterations in the prefrontal cortex implicate proteome instability and accumulation of misfolded proteins. Altered mitochondrial dynamics, especially in proteostasis processes, could impede the normal compensatory mechanisms against cell damage. Thereby, altered mitochondrial functions on regulatory modulation of dendritic development, neuroinflammation, and respiratory function may underlie the development of some psychiatric conditions, such as schizophrenia, being influenced by a genetic background. It is expected that with the increasing evidence about proteostasis in neuropsychiatric disorders, new therapeutic alternatives will emerge.

scholarly journals Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention

2018 ◽  
Vol 46 (4) ◽  
pp. 829-842 ◽  
Author(s):  
Thomas Briston ◽  
Amy R. Hicks
Keyword(s):  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Metabolic Dysfunction ◽  
Loss Of Function ◽  
Deubiquitinating Enzymes ◽  
Cell Death Pathways ◽  
Intervention Point ◽  
Ubiquitin Proteasome ◽  
Atp Supply

Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.

scholarly journals An F-Box Protein, Mdm30, Interacts with TREX Subunit Sub2 To Regulate Cellular Abundance Cotranscriptionally in Orchestrating mRNA Export Independently of Splicing and Mitochondrial Function

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jannatul Ferdoush ◽  
Rwik Sen ◽  
Geetha Durairaj ◽  
Priyanka Barman ◽  
Amala Kaja ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mrna Export ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Dependent Manner ◽  
Direct Role ◽  
Transcriptional Inhibition ◽  
Ubiquitin Proteasome ◽  
F Box Protein

ABSTRACT Although an F-box protein, Mdm30, is found to regulate ubiquitylation of the Sub2 component of TREX (transcription-export) complex for proteasomal degradation in stimulation of mRNA export, it remains unknown whether such ubiquitin-proteasome system (UPS) regulation of Sub2 occurs cotranscriptionally via its interaction with Mdm30. Further, it is unclear whether impaired UPS regulation of Sub2 in the absence of Mdm30 alters mRNA export via splicing defects of export factors and/or mitochondrial dynamics/function, since Sub2 controls mRNA splicing and Mdm30 regulates mitochondrial aggregation. Here, we show that Mdm30 interacts with Sub2, and temporary shutdown of Mdm30 enhances Sub2’s abundance and impairs mRNA export. Likewise, Sub2’s abundance is increased following transcriptional inhibition. These results support Mdm30’s direct role in regulation of Sub2’s cellular abundance in a transcription-dependent manner. Consistently, the chromatin-bound Sub2 level is increased in the absence of Mdm30. Further, we find that Mdm30 does not facilitate splicing of export factors. Moreover, Mdm30 does not have a dramatic effect on mitochondrial respiration/function, and mRNA export occurs in the absence of Fzo1, which is required for mitochondrial dynamics/respiration. Collective results reveal that Mdm30 interacts with Sub2 for proteasomal degradation in a transcription-dependent manner to promote mRNA export independently of splicing or mitochondrial function, thus advancing our understanding of mRNA export.

scholarly journals Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission

2013 ◽  
Vol 24 (5) ◽  
pp. 659-667 ◽  
Author(s):  
Oliver C. Losón ◽  
Zhiyin Song ◽  
Hsiuchen Chen ◽  
David C. Chan
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Related Protein ◽  
Immunofluorescence Analysis ◽  
Multiple Receptors ◽  
Mitochondrial Elongation

Several mitochondrial outer membrane proteins—mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively)—have been proposed to promote mitochondrial fission by recruiting the GTPase dynamin-related protein 1 (Drp1), but fundamental issues remain concerning their function. A recent study supported such a role for Mff but not for Fis1. In addition, it is unclear whether MiD49 and MiD51 activate or inhibit fission, because their overexpression causes extensive mitochondrial elongation. It is also unknown whether these proteins can act in the absence of one another to mediate fission. Using Fis1-null, Mff-null, and Fis1/Mff-null cells, we show that both Fis1 and Mff have roles in mitochondrial fission. Moreover, immunofluorescence analysis of Drp1 suggests that Fis1 and Mff are important for the number and size of Drp1 puncta on mitochondria. Finally, we find that either MiD49 or MiD51 can mediate Drp1 recruitment and mitochondrial fission in the absence of Fis1 and Mff. These results demonstrate that multiple receptors can recruit Drp1 to mediate mitochondrial fission.

scholarly journals Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yujie Song ◽  
Yuerong Xu ◽  
Yingying Liu ◽  
Jie Gao ◽  
Lele Feng ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Normal Function ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Dynamic ◽  
Profound Influence ◽  
Ubiquitin Proteasome ◽  
And Function ◽  
The Relationship

Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.

scholarly journals A protein quality control pathway at the mitochondrial outer membrane

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Meredith B Metzger ◽  
Jessica L Scales ◽  
Mitchell F Dunklebarger ◽  
Jadranka Loncarek ◽  
Allan M Weissman
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Outer Membrane ◽  
Temperature Sensitive ◽  
Aaa Atpase ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Proteasome ◽  
Novel Model

Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires the SSA family of Hsp70s and the Hsp40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways.

scholarly journals Selective targeting of non-centrosomal AURKA functions through use of a novel targeted protein degradation tool

2020 ◽  
Author(s):  
Richard Wang ◽  
Ahmed Abdelbaki ◽  
Camilla Ascanelli ◽  
Alex Fung ◽  
Tim Rasmusson ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cell Biology ◽  
Mitochondrial Dynamics ◽  
Functional Characterization ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Modality ◽  
System A ◽  
Small Molecule Ligands ◽  
Ubiquitin Proteasome ◽  
Clinical Interest

AbstractTargeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (referred to as ‘PROTACs’, for PROteolysis Targeting Chimeras) that recruit a ubiquitin ligase to the target of interest, leading to ubiquitination of the target and its destruction via the ubiquitin-proteasome system. A number of PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate the centrosome- and chromatin-based microtubule spindle assembly pathways. In interphase cells we find that PROTAC-mediated clearance of non-centrosomal AURKA, and not PROTAC-mediated inhibition of its activity, efficiently modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential accessibility of subcellular pools of substrate, governed by substrate conformation or localization in compartments more or less accessible to PROTAC action, a phenomenon not previously described for this new class of drugs.

scholarly journals Protein Quality Control at the Mitochondrial Surface

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabian den Brave ◽  
Arushi Gupta ◽  
Thomas Becker
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Outer Membrane Proteins ◽  
Tom Complex ◽  
Cellular Environment ◽  
Mitochondrial Functions ◽  
Precursor Proteins

Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

Sign in / Sign up

Export Citation Format

Share Document