Mitochondria-Associated Proteostasis

2020 ◽  
Vol 49 (1) ◽  
pp. 41-67 ◽  
Author(s):  
Linhao Ruan ◽  
Yuhao Wang ◽  
Xi Zhang ◽  
Alexis Tomaszewski ◽  
Joshua T. McNamara ◽  
...  
Keyword(s):  
Quality Control ◽  
Cardiovascular Diseases ◽  
Protein Quality ◽  
Therapeutic Potential ◽  
Nuclear Genome ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Mitochondrial Proteome ◽  
Functional States

Mitochondria are essential organelles in eukaryotes. Most mitochondrial proteins are encoded by the nuclear genome and translated in the cytosol. Nuclear-encoded mitochondrial proteins need to be imported, processed, folded, and assembled into their functional states. To maintain protein homeostasis (proteostasis), mitochondria are equipped with a distinct set of quality control machineries. Deficiencies in such systems lead to mitochondrial dysfunction, which is a hallmark of aging and many human diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancer. In this review, we discuss the unique challenges and solutions of proteostasis in mitochondria. The import machinery coordinates with mitochondrial proteases and chaperones to maintain the mitochondrial proteome. Moreover, mitochondrial proteostasis depends on cytosolic protein quality control mechanisms during crises. In turn, mitochondria facilitate cytosolic proteostasis. Increasing evidence suggests that enhancing mitochondrial proteostasis may hold therapeutic potential to protect against protein aggregation–associated cellular defects.

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 Organismal Protein Homeostasis Mechanisms

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Thorsten Hoppe ◽  
Ehud Cohen
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Dynamic Regulation ◽  
C Elegans ◽  
Selective Degradation ◽  
Proteotoxic Stress ◽  
Health And Disease ◽  
Folded Proteins

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

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

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.

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

Molecules ◽  
2018 ◽  
Vol 23 (5) ◽  
pp. 1219 ◽  
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

scholarly journals Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

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

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.

scholarly journals The Dual Origin of the Yeast Mitochondrial Proteome

Yeast ◽  
2000 ◽  
Vol 1 (3) ◽  
pp. 170-187 ◽  
Author(s):  
Olof Karlberg ◽  
Björn Canbäck ◽  
Charles G. Kurland ◽  
Siv G. E. Andersson
Keyword(s):  
Nuclear Genome ◽  
Mitochondrial Proteins ◽  
Mitochondrial Proteome ◽  
Phylogenetic Reconstructions ◽  
Eukaryotic Genes ◽  
Genes Encoding ◽  
Parallel Mode ◽  
Bacterial Genes ◽  
Dual Origin ◽  
Regulatory Functions

We propose a scheme for the origin of mitochondria based on phylogenetic reconstructions with more than 400 yeast nuclear genes that encode mitochondrial proteins. Half of the yeast mitochondrial proteins have no discernable bacterial homologues, while one-tenth are unequivocally of α-proteobacterial origin. These data suggest that the majority of genes encoding yeast mitochondrial proteins are descendants of two different genomic lineages that have evolved in different modes. First, the ancestral free-living α-proteobacterium evolved into an endosymbiont of an anaerobic host. Most of the ancestral bacterial genes were lost, but a small fraction of genes supporting bioenergetic and translational processes were retained and eventually transferred to what became the host nuclear genome. In a second, parallel mode, a larger number of novel mitochondrial genes were recruited from the nuclear genome to complement the remaining genes from the bacterial ancestor. These eukaryotic genes, which are primarily involved in transport and regulatory functions, transformed the endosymbiont into an ATP-exporting organelle.

scholarly journals CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark J. Ranek ◽  
Christian Oeing ◽  
Rebekah Sanchez-Hodge ◽  
Kristen M. Kokkonen-Simon ◽  
Danielle Dillard ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Kinase ◽  
Protein Quality ◽  
Therapeutic Potential ◽  
Protein Quality Control ◽  
Ischemic Injury ◽  
Protein Kinase G ◽  
Interacting Protein ◽  
Important Regulator

Abstract Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.

scholarly journals Long-Term Recreational Football Training and Health in Aging

2020 ◽  
Vol 17 (6) ◽  
pp. 2087
Author(s):  
Esther Imperlini ◽  
Annamaria Mancini ◽  
Stefania Orrù ◽  
Daniela Vitucci ◽  
Valeria Di Onofrio ◽  
...  
Keyword(s):  
Quality Control ◽  
Dna Repair ◽  
Successful Aging ◽  
Protein Quality ◽  
Metabolic Diseases ◽  
Control Mechanisms ◽  
Older Subjects ◽  
Football Training ◽  
Over Time

This narrative review aims to critically analyze the effects of exercise on health in aging. Here we discuss the main clinical and biomolecular modifications induced by long-term recreational football training in older subjects. In particular, the effects induced by long-term recreational football training on cardiovascular, metabolic and musculo-skeletal fitness, together with the modifications in the muscle expression of hallmarks related to oxidative metabolism, DNA repair and senescence suppression pathways and protein quality control mechanisms will be provided. All these topics will be debated also in terms of preventing non-communicable metabolic diseases, in order to achieve successful aging over time.

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.

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