Protein quality control at the mitochondrion

2016 ◽  
Vol 60 (2) ◽  
pp. 213-225 ◽  
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.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Protein quality control in the secretory pathway

2019 ◽  
Vol 218 (10) ◽  
pp. 3171-3187 ◽  
Author(s):  
Zhihao Sun ◽  
Jeffrey L. Brodsky
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Unfolded Protein ◽  
Protein Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.

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.

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.

LonP1 Links UPRmt and UPRER to Regulate Heart Function

2021 ◽  
Author(s):  
Yujie Li ◽  
Dawei Huang ◽  
Fugen Shangguan ◽  
Lianqun Jia ◽  
Linhua Lan ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Heart Function ◽  
Mitochondrial Dynamics ◽  
Protein Quality Control ◽  
Metabolic Reprogramming ◽  
The Novel ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Protein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRER and UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRER remains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRER and UPRmt is substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRER occurs earlier than UPRmt in response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. We uncovered the novel function of LonP1 as an UPRmt mediator, and reciprocal orchestration of UPRmt and UPRER and mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

scholarly journals LonP1 Orchestrates UPRmtand UPRERand Mitochondrial Dynamics to Regulate Heart Function

2019 ◽  
Author(s):  
Bin Lu ◽  
Fugen Shangguan ◽  
Dawei Huang ◽  
Shiwei Gong ◽  
Yingchao Shi ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Heart Function ◽  
Mitochondrial Dynamics ◽  
Protein Quality Control ◽  
Metabolic Reprogramming ◽  
The Novel ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractProtein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRERand UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRERremains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRERand UPRmtis substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRERoccurs earlier than UPRmtin response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. Thus, we uncovered the novel function of LonP1 as an UPRmtmediator, and reciprocal orchestration of UPRmtand UPRERand mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

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 The UPR in Neurodegenerative Disease: Not Just an Inside Job

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1090
Author(s):  
Anna Maria van Ziel ◽  
Wiep Scheper
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Long Distance ◽  
Unfolded Protein ◽  
Long Distance Transport ◽  
Cell Type Specific ◽  
Membrane Bound ◽  
The Unfolded Protein Response ◽  
Protein Response

Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases.

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