Molecular pathways of mitochondrial outer membrane protein degradation

2019 ◽  
Vol 47 (5) ◽  
pp. 1437-1447 ◽  
Author(s):  
Jing Zheng ◽  
Lanlan Li ◽  
Hui Jiang
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Outer Membrane ◽  
Protein Import ◽  
Protein Quality ◽  
Mitochondrial Outer Membrane ◽  
Molecular Pathways ◽  
Precursor Proteins ◽  
Cytoplasmic Signals ◽  
Aaa Atpases

Abstract Mitochondrial outer membrane (MOM) encloses inner compartments of mitochondria and integrates cytoplasmic signals to regulate essential mitochondrial processes, such as protein import, dynamics, metabolism, cell death, etc. A substantial understanding of MOM associated proteostatic stresses and quality control pathways has been obtained in recent years. Six MOM associated protein degradation (MAD) pathways center on three AAA ATPases: Cdc48 in the cytoplasm, Msp1 integral to MOM, and Yme1 integral to the inner membrane. These pathways survey MOM proteome from the cytoplasmic and the inter-membrane space (IMS) sides. They detect and degrade MOM proteins with misfolded cytoplasmic and IMS domains, remove mistargeted tail-anchored proteins, and clear mitochondrial precursor proteins clogged in the TOM import complex. These MOM associated protein quality control pathways collaboratively maintain mitochondrial proteostasis and cell viability.

scholarly journals An essential novel component of the noncanonical mitochondrial outer membrane protein import system of trypanosomatids

2012 ◽  
Vol 23 (17) ◽  
pp. 3420-3428 ◽  
Author(s):  
Mascha Pusnik ◽  
Jan Mani ◽  
Oliver Schmidt ◽  
Moritz Niemann ◽  
Silke Oeljeklaus ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Protein Import ◽  
Matrix Proteins ◽  
Mitochondrial Outer Membrane ◽  
Outer Mitochondrial Membrane ◽  
Precursor Proteins ◽  
Substrate Proteins ◽  
Import System

The mitochondrial outer membrane protein Tom40 is the general entry gate for imported proteins in essentially all eukaryotes. Trypanosomatids lack Tom40, however, and use instead a protein termed the archaic translocase of the outer mitochondrial membrane (ATOM). Here we report the discovery of pATOM36, a novel essential component of the trypanosomal outer membrane protein import system that interacts with ATOM. pATOM36 is not related to known Tom proteins from other organisms and mediates the import of matrix proteins. However, there is a group of precursor proteins whose import is independent of pATOM36. Domain-swapping experiments indicate that the N-terminal presequence-containing domain of the substrate proteins at least in part determines the dependence on pATOM36. Secondary structure profiling suggests that pATOM36 is composed largely of α-helices and its assembly into the outer membrane is independent of the sorting and assembly machinery complex. Taken together, these results show that pATOM36 is a novel component associated with the ATOM complex that promotes the import of a subpopulation of proteins into the mitochondrial matrix.

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

2020 ◽  
Author(s):  
Meredith B Metzger ◽  
Jessica L Scales ◽  
Mitchell F Dunklebarger ◽  
Jadranka Loncarek ◽  
Allan M Weissman
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Author Response ◽  
Mitochondrial Outer Membrane

scholarly journals Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

2020 ◽  
Author(s):  
Prasad Sulkshane ◽  
Jonathan Ram ◽  
Michael H Glickman
Keyword(s):  
Quality Control ◽  
Protein Import ◽  
Protein Quality ◽  
Outer Membrane Proteins ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Cell Protein ◽  
Mitochondrial Outer Membrane ◽  
Control Mechanisms ◽  
Protein Ubiquitination

Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The Ubiquitin-Proteasome System (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the ER and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination have remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for the basal function of mitochondria, metabolic implications, and possible therapeutic applications.

scholarly journals Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1559
Author(s):  
Prasad Sulkshane ◽  
Jonathan Ram ◽  
Michael H Glickman
Keyword(s):  
Quality Control ◽  
Protein Import ◽  
Protein Quality ◽  
Outer Membrane Proteins ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Cell Protein ◽  
Mitochondrial Outer Membrane ◽  
Control Mechanisms ◽  
Protein Ubiquitination

Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The ubiquitin-proteasome system (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the Endoplasmic Reticulum (ER) and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination has remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial protein import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for basal function of mitochondria, metabolic implications, and possible therapeutic applications.

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 Role of Phosphatidylethanolamine in the Biogenesis of Mitochondrial Outer Membrane Proteins

2013 ◽  
Vol 288 (23) ◽  
pp. 16451-16459 ◽  
Author(s):  
Thomas Becker ◽  
Susanne E. Horvath ◽  
Lena Böttinger ◽  
Natalia Gebert ◽  
Günther Daum ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Proper Function ◽  
Mitochondrial Outer Membrane ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Helical Proteins ◽  
The Stability

The mitochondrial outer membrane contains proteinaceous machineries for the import and assembly of proteins, including TOM (translocase of the outer membrane) and SAM (sorting and assembly machinery). It has been shown that the dimeric phospholipid cardiolipin is required for the stability of TOM and SAM complexes and thus for the efficient import and assembly of β-barrel proteins and some α-helical proteins of the outer membrane. Here, we report that mitochondria deficient in phosphatidylethanolamine (PE), the second non-bilayer-forming phospholipid, are impaired in the biogenesis of β-barrel proteins, but not of α-helical outer membrane proteins. The stability of TOM and SAM complexes is not disturbed by the lack of PE. By dissecting the import steps of β-barrel proteins, we show that an early import stage involving translocation through the TOM complex is affected. In PE-depleted mitochondria, the TOM complex binds precursor proteins with reduced efficiency. We conclude that PE is required for the proper function of the TOM complex.

scholarly journals The nucleus is a quality control center for non-imported mitochondrial proteins

2020 ◽  
Author(s):  
Viplendra P.S. Shakya ◽  
William A. Barbeau ◽  
Tianyao Xiao ◽  
Christina S. Knutson ◽  
Adam L. Hughes
Keyword(s):  
Quality Control ◽  
Steady State ◽  
Nuclear Protein ◽  
Protein Quality ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Mitochondrial Import ◽  
Control Center ◽  
Mitochondrial Impairment ◽  
Precursor Proteins

AbstractMitochondrial import deficiency causes cellular stress due to the accumulation of non-imported mitochondrial precursor proteins. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we catalog the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We find that a number of non-imported mitochondrial proteins localize to the nucleus, where they are eliminated by proteasome-based nuclear protein quality control. Recognition of mitochondrial precursors by the nuclear quality control machinery requires the presence of an N-terminal mitochondrial targeting sequence (MTS), and impaired breakdown of precursors leads to their buildup in nuclear-associated foci. These results identify the nucleus as a key destination for the disposal of non-imported mitochondrial precursors.

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.

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