scholarly journals Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gian-Luca McLelland ◽  
Thomas Goiran ◽  
Wei Yi ◽  
Geneviève Dorval ◽  
Carol X Chen ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Membrane ◽  
Facilitatory Effect ◽  
Major Portion ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Contact Sites ◽  
A Cell ◽  
Dependent Mechanism

Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites.

Msp1/ATAD1 in Protein Quality Control and Regulation of Synaptic Activities

2020 ◽  
Vol 36 (1) ◽  
pp. 141-164
Author(s):  
Lan Wang ◽  
Peter Walter
Keyword(s):  
Quality Control ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Quality ◽  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Neurotransmitter Receptors ◽  
Functional Specialization ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import

Mitochondrial function depends on the efficient import of proteins synthesized in the cytosol. When cells experience stress, the efficiency and faithfulness of the mitochondrial protein import machinery are compromised, leading to homeostatic imbalances and damage to the organelle. Yeast Msp1 (mitochondrial sorting of proteins 1) and mammalian ATAD1 (ATPase family AAA domain–containing 1) are orthologous AAA proteins that, fueled by ATP hydrolysis, recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. Msp1 also extracts proteins that have become stuck in the import channel. The extracted proteins are targeted for proteasome-dependent degradation or, in the case of mistargeted tail-anchored proteins, are given another chance to be routed correctly. In addition, ATAD1 is implicated in the regulation of synaptic plasticity, mediating the release of neurotransmitter receptors from postsynaptic scaffolds to allow their trafficking. Here we discuss how structural and functional specialization imparts the unique properties that allow Msp1/ATAD1 ATPases to fulfill these diverse functions and also highlight outstanding questions in the field.

scholarly journals Ubiquitination of the yeast receptor Atg32 modulates mitophagy

2019 ◽  
Author(s):  
Pierre Vigié ◽  
Cécile Gonzalez ◽  
Stephen Manon ◽  
Ingrid Bhatia-Kissova ◽  
Nadine Camougrand
Keyword(s):  
Mass Spectrometry ◽  
Quality Control ◽  
Stationary Phase ◽  
Proteolytic Activity ◽  
Posttranslational Modifications ◽  
Protein Level ◽  
Mitochondrial Membrane ◽  
Mass Spectrometry Analysis ◽  
Outer Mitochondrial Membrane ◽  
Spectrometry Analysis

AbstractMitophagy, the process that degrades mitochondria selectively through autophagy, is involved in the quality control of these organelles. In yeast, the presence of the Atg32 protein on the outer mitochondrial membrane allows for the recognition and targeting of superfluous or damaged mitochondria for degradation. Some posttranslational modifications, such as phosphorylation, are crucial for the execution of the mitophagy process. In our study, we showed that in the stationary phase of growth, and to a lesser extent during starvation, the Atg32 protein level decreases. The fact that a decline in Atg32 level can be prevented by inhibition of the proteolytic activity of proteasome may indicate that Atg32 is also ubiquitylated. In fact, mass spectrometry analysis of purified Atg32 protein showed ubiquitination of lysine residue in position 282. These different patterns of posttranslational modifications of Atg32 could allow cells to control the mitophagy process carefully.

scholarly journals Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 598 ◽  
Author(s):  
Anna Picca ◽  
Riccardo Calvani ◽  
Hélio José Coelho-Junior ◽  
Francesco Landi ◽  
Roberto Bernabei ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Age Related ◽  
Bidirectional Communication ◽  
Membrane Contact ◽  
Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

scholarly journals Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Prospective Roles in Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Peng Gao ◽  
Wenxia Yang ◽  
Lin Sun
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Future Research ◽  
Inflammasome Activation ◽  
Mitochondrial Quality Control ◽  
Downstream Signaling ◽  
Contact Sites ◽  
Progression Of Kidney Disease

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for interorganelle communication in eukaryotic cells and play multifunctional roles in various biological pathways. A defect in ER-mitochondria signaling or MAMs dysfunction has pleiotropic effects on a variety of intracellular events, which results in disturbances of the mitochondrial quality control system, Ca2+ dyshomeostasis, apoptosis, ER stress, and inflammasome activation, which all contribute to the onset and progression of kidney disease. Here, we review the structure and molecular compositions of MAMs as well as the experimental methods used to study these interorganellar contact sites. We will specifically summarize the downstream signaling pathways regulated by MAMs, mainly focusing on mitochondrial quality control, oxidative stress, ER-mitochondria Ca2+ crosstalk, apoptosis, inflammasome activation, and ER stress. Finally, we will discuss how alterations in MAMs integrity contribute to the pathogenesis of kidney disease and offer directions for future research.

Mitochondrial quality control by the ubiquitin–proteasome system

2011 ◽  
Vol 39 (5) ◽  
pp. 1509-1513 ◽  
Author(s):  
Eric B. Taylor ◽  
Jared Rutter
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Ubiquitinated Proteins ◽  
Ubiquitin Proteasome

Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondria-associated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle 42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights into the interaction of the UPS (ubiquitin–proteasome system) with the OMM. In yeast, Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97 to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy. Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the maintenance of cellular and therefore organismal viability.

scholarly journals Capture and delivery of tail-anchored proteins to the endoplasmic reticulum

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Ákos Farkas ◽  
Katherine E. Bohnsack
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Transmembrane Segment ◽  
Cellular Functions ◽  
Protein Capture ◽  
Major Route ◽  
Alternative Routes ◽  
Ta Proteins

Tail-anchored (TA) proteins fulfill diverse cellular functions within different organellar membranes. Their characteristic C-terminal transmembrane segment renders TA proteins inherently prone to aggregation and necessitates their posttranslational targeting. The guided entry of TA proteins (GET in yeast)/transmembrane recognition complex (TRC in humans) pathway represents a major route for TA proteins to the endoplasmic reticulum (ER). Here, we review important new insights into the capture of nascent TA proteins at the ribosome by the GET pathway pretargeting complex and the mechanism of their delivery into the ER membrane by the GET receptor insertase. Interestingly, several alternative routes by which TA proteins can be targeted to the ER have emerged, raising intriguing questions about how selectivity is achieved during TA protein capture. Furthermore, mistargeting of TA proteins is a fundamental cellular problem, and we discuss the recently discovered quality control machineries in the ER and outer mitochondrial membrane for displacing mislocalized TA proteins.

scholarly journals The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis.

2003 ◽  
Vol 50 (2) ◽  
pp. 389-404 ◽  
Author(s):  
Mikhail Y Vyssokikh ◽  
Dieter Brdiczka
Keyword(s):  
Creatine Kinase ◽  
Cytochrome C ◽  
Mitochondrial Membrane ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Outer Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
Membrane Pore ◽  
Contact Sites

The outer mitochondrial membrane pore (VDAC) changes its structure either voltage-dependently in artificial membranes or physiologically by interaction with the adenine nucleotide translocase (ANT) in the c-conformation. This interaction creates contact sites and leads in addition to a specific organisation of cytochrome c in the VDAC-ANT complexes. The VDAC structure that is specific for contact sites generates a signal at the surface for several proteins in the cytosol to bind with high capacity, such as hexokinase, glycerol kinase and Bax. If the VDAC binding site is not occupied by hexokinase, the VDAC-ANT complex has two critical qualities: firstly, Bax gets access to cytochrome c and secondly the ANT is set in its c-conformation that easily changes conformation into an unspecific channel (uniporter) causing permeability transition. Activity of bound hexokinase protects against both, it hinders Bax binding and employs the ANT as anti-porter. The octamer of mitochondrial creatine kinase binds to VDAC from the inner surface of the outer membrane. This firstly restrains interaction between VDAC and ANT and secondly changes the VDAC structure into low affinity for hexokinase and Bax. Cytochrome c in the creatine kinase complex will be differently organised, not accessible to Bax and the ANT is run as anti-porter by the active creatine kinase octamer. However, when, for example, free radicals cause dissociation of the octamer, VDAC interacts with the ANT with the same results as described above: Bax-dependent cytochrome c release and risk of permeability transition pore opening.

The role of contact sites between inner and outer mitochondrial membrane in energy transfer

1990 ◽  
Vol 1018 (2-3) ◽  
pp. 229-233 ◽  
Author(s):  
Klaas Nicolay ◽  
Manuel Rojo ◽  
Theo Wallimann ◽  
Rudy Demel ◽  
Ruud Hovius
Keyword(s):  
Energy Transfer ◽  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Contact Sites

scholarly journals The Interplay among PINK1/PARKIN/Dj-1 Network during Mitochondrial Quality Control in Cancer Biology: Protein Interaction Analysis

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 154 ◽  
Author(s):  
Celia Salazar ◽  
Paula Ruiz-Hincapie ◽  
Lina Ruiz
Keyword(s):  
Quality Control ◽  
Protein Interactions ◽  
Cancer Biology ◽  
Mitochondrial Membrane ◽  
Interaction Analysis ◽  
Enrichment Analysis ◽  
Mitochondrial Morphology ◽  
Transcriptional Level ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Quality Control

PARKIN (E3 ubiquitin ligase PARK2), PINK1 (PTEN induced kinase 1) and DJ-1 (PARK7) are proteins involved in autosomal recessive parkinsonism, and carcinogenic processes. In damaged mitochondria, PINK1’s importing into the inner mitochondrial membrane is prevented, PARKIN presents a partial mitochondrial localization at the outer mitochondrial membrane and DJ-1 relocates to mitochondria when oxidative stress increases. Depletion of these proteins result in abnormal mitochondrial morphology. PINK1, PARKIN, and DJ-1 participate in mitochondrial remodeling and actively regulate mitochondrial quality control. In this review, we highlight that PARKIN, PINK1, and DJ-1 should be regarded as having an important role in Cancer Biology. The STRING database and Gene Ontology (GO) enrichment analysis were performed to consolidate knowledge of well-known protein interactions for PINK1, PARKIN, and DJ-1 and envisage new ones. The enrichment analysis of KEGG pathways showed that the PINK1/PARKIN/DJ-1 network resulted in Parkinson disease as the main feature, while the protein DJ-1 showed enrichment in prostate cancer and p53 signaling pathway. Some predicted transcription factors regulating PINK1, PARK2 (PARKIN) and PARK7 (DJ-1) gene expression are related to cell cycle control. We can therefore suggest that the interplay among PINK1/PARKIN/DJ-1 network during mitochondrial quality control in cancer biology may occur at the transcriptional level. Further analysis, like a systems biology approach, will be helpful in the understanding of PINK1/PARKIN/DJ-1 network.

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