scholarly journals Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

2021 ◽  
Vol 23 (1) ◽  
pp. 7
Author(s):  
Anna M. Lenkiewicz ◽  
Magda Krakowczyk ◽  
Piotr Bragoszewski
Keyword(s):  
Quality Control ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Ubiquitin Proteasome System ◽  
Vital Role ◽  
Protein Homeostasis ◽  
Organelle Biogenesis ◽  
Mitochondrial Protein Import ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways

With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

scholarly journals Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

2020 ◽  
Vol 295 (30) ◽  
pp. 10138-10152 ◽  
Author(s):  
Janin Lautenschläger ◽  
Sara Wagner-Valladolid ◽  
Amberley D. Stephens ◽  
Ana Fernández-Villegas ◽  
Colin Hockings ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Protein Import ◽  
Protein Quality ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Mitochondrial Inhibitors ◽  
Ubiquitin Proteasome

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

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 Mitochondrial Protein Quality Control Mechanisms

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 563 ◽  
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.

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 Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating other proteins aggregation

2021 ◽  
Author(s):  
Urszula Nowicka ◽  
Piotr Chroscicki ◽  
Karen Stroobants ◽  
Maria Sladowska ◽  
Michal Turek ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Mitochondrial Protein Import ◽  
Protein Levels ◽  
Proteotoxic Stress ◽  
Encoded Proteins ◽  
Related Proteins

Mitochondria are organelles with their own genomes but rely on the import of nuclear-encoded proteins synthesized by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins may cause proteotoxic stress, and to identify which response mechanisms may be in place to respond to it. Here, we report that upon mitochondrial protein import impairment, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. In turn, these deposits cause further cytosolic accumulation of other mitochondrial and disease-related proteins, including α-synuclein and amyloid β. This aberrant accumulation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses, both at the transcriptomic and protein levels. Our results provide evidence that mitochondrial dysfunction, and specifically protein import defects, can contribute to protein homeostasis impairment, thus revealing a possible molecular mechanism for mitochondrial involvement in neurodegenerative diseases.

scholarly journals Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Urszula Nowicka ◽  
Piotr Chroscicki ◽  
Karen Stroobants ◽  
Maria Sladowska ◽  
Michal Turek ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Mitochondrial Protein Import ◽  
Protein Levels ◽  
Proteotoxic Stress ◽  
Encoded Proteins ◽  
Related Proteins

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

scholarly journals Mitochondrial protein import regulates cytosolic protein homeostasis and neuronal integrity

Autophagy ◽  
2018 ◽  
Vol 14 (8) ◽  
pp. 1293-1309 ◽  
Author(s):  
Wei Liu ◽  
Xiuying Duan ◽  
Xuefei Fang ◽  
Weina Shang ◽  
Chao Tong
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Protein Homeostasis ◽  
Mitochondrial Protein Import ◽  
Cytosolic Protein

scholarly journals Mistargeting of hydrophobic mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes

2021 ◽  
Author(s):  
Caroline E. Dewar ◽  
Silke Oeljeklaus ◽  
Jan Mani ◽  
Wignand W. D. Mühlhäuser ◽  
Bettina Warscheid ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Import ◽  
Nuclear Protein ◽  
Mitochondrial Protein ◽  
Protein A ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Quality Control ◽  
Import Receptor

Mitochondrial protein import in the parasitic protozoan Trypanosoma brucei is mediated by the atypical outer membrane translocase, ATOM. It consists of seven subunits including ATOM69, the import receptor for hydrophobic proteins. Ablation of ATOM69, but not of any other subunit, triggers a unique quality control pathway resulting in the proteasomal degradation of non-imported mitochondrial proteins. The process requires a protein of unknown function, an E3 ubiquitin ligase and the ubiquitin-like protein (TbUbL1), which all are recruited to the mitochondrion upon ATOM69 depletion. TbUbL1 is a nuclear protein, a fraction of which is released to the cytosol upon triggering of the pathway. Nuclear release is essential as cytosolic TbUbL1 can bind mislocalised mitochondrial proteins and likely transfers them to the proteasome. Mitochondrial quality control has previously been studied in yeast and metazoans. Finding such a pathway in the highly diverged trypanosomes suggests such pathways are an obligate feature of all mitochondria.

scholarly journals Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology

2019 ◽  
Author(s):  
Janin Lautenschläger ◽  
Sara Wagner-Valladolid ◽  
Amberley D. Stephens ◽  
Ana Fernández-Villegas ◽  
Colin Hockings ◽  
...  
Keyword(s):  
Calcium Concentration ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Alpha Synuclein ◽  
Protein Homeostasis ◽  
Oxygen Species ◽  
Direct Inhibition ◽  
Mitochondrial Protein Import ◽  
Alpha Synuclein Aggregation

AbstractMitochondria have long been implicated in Parkinson’s disease (PD), however, it is not clear how mitochondrial impairment and alpha-synuclein pathology are coupled. We report here that intra-mitochondrial protein homeostasis plays a major role in alpha-synuclein fibril elongation, as interference with intra-mitochondrial proteases and mitochondrial protein import significantly aggravate alpha-synuclein aggregation. In contrast, direct inhibition of mitochondrial complex I, increase in intracellular calcium concentration or formation of reactive oxygen species (ROS), all of which have been associated with mitochondrial stress, did not affect alpha-synuclein pathology. We further demonstrate that similar mechanisms are involved in Amyloid β 1-42 (Aβ42) aggregation, suggesting that mitochondria are directly capable of influencing cytosolic protein homeostasis of aggregation-prone proteins.

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