Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

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.

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Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

10.20944/preprints202010.0512.v1 ◽

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.

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Mitochondrial Protein Quality Control Mechanisms

Genes ◽

10.3390/genes11050563 ◽

2020 ◽

Vol 11 (5) ◽

pp. 563 ◽

Cited By ~ 4

Author(s):

Pooja Jadiya ◽

Dhanendra Tomar

Keyword(s):

Quality Control ◽

Protein Import ◽

Protein Quality ◽

Current Knowledge ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Redox Balance ◽

Ubiquitin Proteasome System ◽

Control Mechanisms ◽

Mitochondrial Proteome

Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.

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Protein quality control at the mitochondrion

Essays in Biochemistry ◽

10.1042/ebc20160009 ◽

2016 ◽

Vol 60 (2) ◽

pp. 213-225 ◽

Cited By ~ 29

Author(s):

Wolfgang Voos ◽

Witold Jaworek ◽

Anne Wilkening ◽

Michael Bruderek

Keyword(s):

Quality Control ◽

Structural Integrity ◽

Protein Quality ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Eukaryotic Cell ◽

Control Mechanisms ◽

Biochemical Processes ◽

Unfolded Protein ◽

Protein Response

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.

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Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

Experimental Biology and Medicine ◽

10.1177/1535370221999812 ◽

2021 ◽

pp. 153537022199981

Author(s):

Chamithi Karunanayake ◽

Richard C Page

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Quality Control ◽

Structural Features ◽

Cellular Protein ◽

Mechanisms Of Action ◽

Control Mechanisms ◽

Nucleotide Exchange ◽

Domain Organization ◽

Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

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Targeting Protein Quality Control Mechanisms by Natural Products to Promote Healthy Ageing

Molecules ◽

10.3390/molecules23051219 ◽

2018 ◽

Vol 23 (5) ◽

pp. 1219 ◽

Cited By ~ 16

Author(s):

Sophia Wedel ◽

Maria Manola ◽

Maria Cavinato ◽

Ioannis Trougakos ◽

Pidder Jansen-Dürr

Keyword(s):

Quality Control ◽

Natural Products ◽

Protein Quality ◽

Protein Quality Control ◽

Healthy Ageing ◽

Control Mechanisms

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Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

Frontiers in Physiology ◽

10.3389/fphys.2020.593585 ◽

2020 ◽

Vol 11 ◽

Author(s):

Sumita Mishra ◽

Brittany L. Dunkerly-Eyring ◽

Gizem Keceli ◽

Mark J. Ranek

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Quality Control ◽

Control Mechanisms

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

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-031220-015840 ◽

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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