scholarly journals IMiQC: a novel protein quality control compartment protecting mitochondrial functional integrity

2016 ◽  
Author(s):  
Michael Bruderek ◽  
Witold Jaworek ◽  
Anne Wilkening ◽  
Cornelia Rüb ◽  
Giovanna Cenini ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Fission ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Proteotoxic Stress ◽  
Endogenous Proteins ◽  
A Minor ◽  
And Function ◽  
Control Compartment

Aggregation processes can cause severe perturbations of cellular homeostasis and are frequently associated with diseases. We performed a comprehensive analysis of mitochondrial quality and function in presence of misfolded, aggregation-prone polypeptides. Although we observed significant aggregate formation inside mitochondria, we observed only a minor impairment of mitochondrial function. We could show that detoxification of misfolded reporter polypeptides as well as endogenous proteins inside mitochondria takes place via their sequestration into the specific organellar deposit site Intra-Mitochondrial Protein Quality Control Compartment (IMiQC). Only minor amounts of co-aggregated proteins were associated with IMiQC and neither resolubilization nor degradation by the mitochondrial PQC system were observed. The single IMiQC aggregate deposit was not transferred to daughter cells during cell division. Detoxification of misfolded polypeptides via IMiQC formation was highly dependent on a functional mitochondrial fission machinery. We conclude that the formation of the aggregate deposit is an important mechanism to maintain full functionality of mitochondria under proteotoxic stress conditions.

Abstract 85: The AAA-ATPase p97 is a Critical Regulator of Cardiac Homeostasis

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Matthew J Brody ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Complexes ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Dominant Negative ◽  
Aaa Atpase ◽  
And Function ◽  
Thrombospondin 4

p97 is a AAA-ATPase that plays critical roles in a myriad of cellular protein quality control processes, including the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway that targets misfolded proteins in the ER for degradation in the cytosol by the ubiquitin proteasome system. Mutations in p97 cause a multisystem degenerative proteinopathy disorder called inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) that includes pathologies of the nervous system, skeletal muscle, bone, and heart. Previous studies in the laboratory into the mechanisms whereby thrombospondin 4 has its cardioprotective effects and enhanced ERAD activity identified p97 as a direct interacting partner. This observation suggested that p97 itself could be an important cardioprotective effector by benefiting protein quality control in the heart. To address this hypothesis here we generated cardiac-specific transgenic mice overexpressing wildtype p97 or a p97 K524A mutant with deficient ATPase activity, the latter of which functioned as a dominant negative. Mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop cardiomyopathy, upregulate several ERAD complex components, and have elevated levels of ubiquitinated proteins. Proteomics and immunoprecipitation assays identified overwhelming interactions between endogenous p97 and a number of interesting protein complexes that suggest unique functions for this protein in regulating protein quality control in the heart. The results and novel regulatory relationships will be presented, which suggests entirely unique pathways whereby p97 functions in the heart.

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.

Mitochondrial protein quality control: Implications in ageing

2008 ◽  
Vol 3 (6) ◽  
pp. 757-764 ◽  
Author(s):  
Bertrand Friguet ◽  
Anne-Laure Bulteau ◽  
Isabelle Petropoulos
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control

scholarly journals Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

2015 ◽  
Vol 22 (12) ◽  
pp. 977-994 ◽  
Author(s):  
Iryna Bohovych ◽  
Sherine S.L. Chan ◽  
Oleh Khalimonchuk
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control

scholarly journals Selective autophagic clearance of protein aggregates is mediated by the autophagy receptor, TAX1BP1

2019 ◽  
Author(s):  
Shireen A. Sarraf ◽  
Hetal V. Shah ◽  
Gil Kanfer ◽  
Michael E. Ward ◽  
Richard J. Youle
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Cellular Homeostasis ◽  
Receptor Proteins ◽  
Proteotoxic Stress ◽  
Polyq Protein ◽  
Ubiquitin Proteasome

AbstractMisfolded protein aggregates can disrupt cellular homeostasis and cause toxicity, a hallmark of numerous neurodegenerative diseases. Protein quality control by the ubiquitin proteasome system (UPS) and autophagy is vital for clearance of aggregates and maintenance of cellular homeostasis1. Autophagy receptor proteins bridge the interaction between ubiquitinated proteins and the autophagy machinery allowing selective elimination of cargo2. Aggrephagy is critical to protein quality control, but how aggregates are recognized and targeted for degradation is not well understood. Here we examine the requirements for 5 autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in proteotoxic stress-induced aggregate clearance. Endogenous TAX1BP1 is both recruited to and required for the clearance of stress-induced aggregates while overexpression of TAX1BP1 increases aggregate clearance through autophagy. Furthermore, TAX1BP1 depletion sensitizes cells to proteotoxic stress and Huntington’s disease-linked polyQ proteins, whereas TAX1BP1 overexpression clears cells of polyQ protein aggregates by autophagy. We propose a broad role for TAX1BP1 in the clearance of cytotoxic proteins, thus identifying a new mode of clearance of protein inclusions.

323-OR: Synergism between Protein Quality Control Pathways to Maintain Alpha-Cell Mass and Function

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 323-OR
Author(s):  
RACHEL B. REINERT ◽  
XIANWEI CUI ◽  
NEHA SHRESTHA ◽  
LING QI
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Cell Mass ◽  
Protein Quality Control ◽  
Alpha Cell ◽  
And Function

scholarly journals Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training

2012 ◽  
Vol 303 (2) ◽  
pp. R127-R134 ◽  
Author(s):  
Erika Koltai ◽  
Nikolett Hart ◽  
Albert W. Taylor ◽  
Sataro Goto ◽  
Jenny K. Ngo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Quality Control ◽  
Exercise Training ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Treadmill Running ◽  
Common Finding ◽  
Moderate Intensity

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate-intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial V̇o2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (succinate dehydrogenase, citrate synthase, cytochrome- c oxidase-4, mtDNA), SIRT1 activity, AMPK, pAMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-α, UCP3, and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters, including nuclear respiratory factor 1, mitochondrial transcription factor A, fission-1, mitofusin-1, and polynucleotide phosphorylase levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

The role of protein quality control in mitochondrial protein homeostasis under oxidative stress

PROTEOMICS ◽  
2010 ◽  
Vol 10 (7) ◽  
pp. 1426-1443 ◽  
Author(s):  
Tom Bender ◽  
Claudia Leidhold ◽  
Thomas Ruppert ◽  
Sebastian Franken ◽  
Wolfgang Voos
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Protein Homeostasis

Increasing organismal healthspan by enhancing mitochondrial protein quality control

2009 ◽  
Vol 11 (7) ◽  
pp. 852-858 ◽  
Author(s):  
Karin Luce ◽  
Heinz D. Osiewacz
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control
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