scholarly journals Protein Quality Control at the Mitochondrial Surface

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabian den Brave ◽  
Arushi Gupta ◽  
Thomas Becker
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Outer Membrane Proteins ◽  
Tom Complex ◽  
Cellular Environment ◽  
Mitochondrial Functions ◽  
Precursor Proteins

Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

scholarly journals Role of Phosphatidylethanolamine in the Biogenesis of Mitochondrial Outer Membrane Proteins

2013 ◽  
Vol 288 (23) ◽  
pp. 16451-16459 ◽  
Author(s):  
Thomas Becker ◽  
Susanne E. Horvath ◽  
Lena Böttinger ◽  
Natalia Gebert ◽  
Günther Daum ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Proper Function ◽  
Mitochondrial Outer Membrane ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Helical Proteins ◽  
The Stability

The mitochondrial outer membrane contains proteinaceous machineries for the import and assembly of proteins, including TOM (translocase of the outer membrane) and SAM (sorting and assembly machinery). It has been shown that the dimeric phospholipid cardiolipin is required for the stability of TOM and SAM complexes and thus for the efficient import and assembly of β-barrel proteins and some α-helical proteins of the outer membrane. Here, we report that mitochondria deficient in phosphatidylethanolamine (PE), the second non-bilayer-forming phospholipid, are impaired in the biogenesis of β-barrel proteins, but not of α-helical outer membrane proteins. The stability of TOM and SAM complexes is not disturbed by the lack of PE. By dissecting the import steps of β-barrel proteins, we show that an early import stage involving translocation through the TOM complex is affected. In PE-depleted mitochondria, the TOM complex binds precursor proteins with reduced efficiency. We conclude that PE is required for the proper function of the TOM complex.

scholarly journals Mitochondrial quality control in intervertebral disc degeneration

2021 ◽  
Author(s):  
Yu Song ◽  
Saideng Lu ◽  
Wen Geng ◽  
Xiaobo Feng ◽  
Rongjin Luo ◽  
...  
Keyword(s):  
Quality Control ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Intervertebral Discs ◽  
Mitochondrial Quality Control

AbstractIntervertebral disc degeneration (IDD) is a common and early-onset pathogenesis in the human lifespan that can increase the risk of low back pain. More clarification of the molecular mechanisms associated with the onset and progression of IDD is likely to help establish novel preventive and therapeutic strategies. Recently, mitochondria have been increasingly recognized as participants in regulating glycolytic metabolism, which has historically been regarded as the main metabolic pathway in intervertebral discs due to their avascular properties. Indeed, mitochondrial structural and functional disruption has been observed in degenerated nucleus pulposus (NP) cells and intervertebral discs. Multilevel and well-orchestrated strategies, namely, mitochondrial quality control (MQC), are involved in the maintenance of mitochondrial integrity, mitochondrial proteostasis, the mitochondrial antioxidant system, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Here, we address the key evidence and current knowledge of the role of mitochondrial function in the IDD process and consider how MQC strategies contribute to the protective and detrimental properties of mitochondria in NP cell function. The relevant potential therapeutic treatments targeting MQC for IDD intervention are also summarized. Further clarification of the functional and synergistic mechanisms among MQC mechanisms may provide useful clues for use in developing novel IDD treatments.

scholarly journals PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 371
Author(s):  
Filipa Barroso Gonçalves ◽  
Vanessa Alexandra Morais
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
High Energy ◽  
Common Denominator ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis ◽  
Cellular Environment ◽  
Familial Form ◽  
Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

scholarly journals A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria

2014 ◽  
Vol 25 (25) ◽  
pp. 3999-4009 ◽  
Author(s):  
Agnieszka Gornicka ◽  
Piotr Bragoszewski ◽  
Piotr Chroscicki ◽  
Lena-Sophie Wenz ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Alternative Pathway ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Membrane Translocation ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Core Components

Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex.

scholarly journals Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 238 ◽  
Author(s):  
Blanca Hernando-Rodríguez ◽  
Marta Artal-Sanz
Keyword(s):  
Quality Control ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Stress Responses ◽  
Membrane Lipids ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Gene ◽  
Control Mechanisms ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Functions

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress, and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the oxidative phosphorylation (OXPHOS) system for ATP production. It requires, in addition, the import of a large number of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue, and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPRmt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial prohibitin (PHB) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Periplasmic quality control in biogenesis of outer membrane proteins

2015 ◽  
Vol 43 (2) ◽  
pp. 133-138 ◽  
Author(s):  
Zhi Xin Lyu ◽  
Xin Sheng Zhao
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Diverse Range ◽  
Multifunctional Protein ◽  
Proposed Model ◽  
Periplasmic Proteins ◽  
Basic Functions ◽  
Biochemical Analyses

The β-barrel outer membrane proteins (OMPs) are integral membrane proteins that reside in the outer membrane of Gram-negative bacteria and perform a diverse range of biological functions. Synthesized in the cytoplasm, OMPs must be transported across the inner membrane and through the periplasmic space before they are assembled in the outer membrane. In Escherichia coli, Skp, SurA and DegP are the most prominent factors identified to guide OMPs across the periplasm and to play the role of quality control. Although extensive genetic and biochemical analyses have revealed many basic functions of these periplasmic proteins, the mechanism of their collaboration in assisting the folding and insertion of OMPs is much less understood. Recently, biophysical approaches have shed light on the identification of the intricate network. In the present review, we summarize recent advances in the characterization of these key factors, with a special emphasis on the multifunctional protein DegP. In addition, we present our proposed model on the periplasmic quality control in biogenesis of OMPs.

scholarly journals The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteins

2011 ◽  
Vol 194 (3) ◽  
pp. 387-395 ◽  
Author(s):  
Thomas Becker ◽  
Lena-Sophie Wenz ◽  
Vivien Krüger ◽  
Waltraut Lehmann ◽  
Judith M. Müller ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Limited Information ◽  
Mitochondrial Import ◽  
Transmembrane Segments ◽  
Membrane Complex ◽  
Complex Functions ◽  
Precursor Proteins

The mitochondrial outer membrane contains translocase complexes for the import of precursor proteins. The translocase of the outer membrane complex functions as a general preprotein entry gate, whereas the sorting and assembly machinery complex mediates membrane insertion of β-barrel proteins of the outer membrane. Several α-helical outer membrane proteins are known to carry multiple transmembrane segments; however, only limited information is available on the biogenesis of these proteins. We report that mitochondria lacking the mitochondrial import protein 1 (Mim1) are impaired in the biogenesis of multispanning outer membrane proteins, whereas overexpression of Mim1 stimulates their import. The Mim1 complex cooperates with the receptor Tom70 in binding of precursor proteins and promotes their insertion and assembly into the outer membrane. We conclude that the Mim1 complex plays a central role in the import of α-helical outer membrane proteins with multiple transmembrane segments.

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