scholarly journals Regulation of mitochondrial proteostasis by the proton gradient

2021 ◽  
Author(s):  
Maria Patron ◽  
Daryna Tarasenko ◽  
Hendrik Nolte ◽  
Mausumi Ghosh ◽  
Yohsuke Ohba ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Mitochondrial Protein ◽  
Proton Gradient ◽  
Turnover Rates ◽  
Mitochondrial Proteome ◽  
Mitochondrial Inner Membrane ◽  
Proteomic Approach ◽  
Adaptive Processes ◽  
Respiratory Complex I ◽  
Gradient Coupling

Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multi-proteomic approach to demonstrate regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+/H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.

scholarly journals Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands

2020 ◽  
Author(s):  
Kyle Swovick ◽  
Denis Firsanov ◽  
Kevin A. Welle ◽  
Jennifer R. Hryhorenko ◽  
John P. Wise ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Protein Misfolding ◽  
Bowhead Whale ◽  
Turnover Rates ◽  
Atp Production ◽  
Proteomic Approach ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Primary Fibroblasts ◽  
Energetic Demand

AbstractCells continually degrade and replace damaged and old proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lives rodent, the naked mole rat and the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

scholarly journals Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands

2020 ◽  
pp. mcp.RA120.002301
Author(s):  
Kyle Swovick ◽  
Denis Firsanov ◽  
Kevin A Welle ◽  
Jennifer Hryhorenko ◽  
John P Wise ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Protein Misfolding ◽  
Bowhead Whale ◽  
Turnover Rates ◽  
Atp Production ◽  
Proteomic Approach ◽  
Mole Rat ◽  
Primary Fibroblasts ◽  
Mouse Cells ◽  
Energetic Demand

Cells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

scholarly journals Generation of a mitochondrial protein compendium in Dictyostelium discoideum

2021 ◽  
Author(s):  
Hong Xu
Keyword(s):  
Dictyostelium Discoideum ◽  
Mitochondrial Protein ◽  
Metabolic Reprogramming ◽  
Mitochondrial Proteins ◽  
Mitochondrial Proteome ◽  
Cellular Processes ◽  
Proteomic Approach ◽  
The Social ◽  
Cellular Pathways ◽  
Alpha Proteobacteria

The social amoeba Dictyostelium discoideum is a well-established model to study numerous cellular processes including cell motility, chemotaxis, and differentiation. As energy metabolism is involved in these processes, mitochondrial genetics and bioenergetics are of interest, though many features of Dictyostelium mitochondria differ from metazoans. A comprehensive inventory of mitochondrial proteins is critical to understanding mitochondrial processes and their involvement in various cellular pathways. Here, we utilized high-throughput multiplexed protein quantitation and homology analyses to generate a high-confidence mitochondrial protein compendium. Our proteomic approach, which utilizes quantitative mass spectrometry in combination with mathematical modeling, was validated through mitochondrial targeting sequence prediction and live-cell imaging. Our final compendium consists of 1082 proteins. Within our D. discoideum mitochondrial proteome, we identify many proteins that are not present in humans, yeasts, or the ancestral alpha-proteobacteria, which can serve as a foundation for future investigations into the unique mitochondria of Dictyostelium. Additionally, we leverage our compendium to highlight the complexity of metabolic reprogramming during starvation-induced development. Our compendium lays a foundation to investigate mitochondrial processes that are unique in protists, as well as for future studies to understand the functions of conserved mitochondrial proteins in health and diseases using D. discoideum as the model.

scholarly journals Regulation of mitochondrial protein turnover by thyroid hormone(s)

1975 ◽  
Vol 152 (2) ◽  
pp. 379-387 ◽  
Author(s):  
Medha S. Rajwade ◽  
Surendra S. Katyare ◽  
Prema Fatterpaker ◽  
Arunachala Sreenivasan
Keyword(s):  
Thyroid Hormone ◽  
Protein Turnover ◽  
Mitochondrial Protein ◽  
Brain Mitochondria ◽  
Mitochondrial Proteins ◽  
Proteinase Activity ◽  
Turnover Rates ◽  
Kidney Mitochondria ◽  
Liver And Kidney ◽  
Protein Components

1. The effect of thyroidectomy on turnover rates of liver, kidney and brain mitochondrial proteins was examined. 2. In the euthyroid state, liver and kidney mitochondria show a synchronous turnover with all protein components showing more or less identical half-lives compared with the whole mitochondria. The brain mitochondrial proteins show asynchronous turnover, the soluble proteins having shorter half-lives. 3. Mitochondrial DNA (m-DNA) of liver and kidney has half-lives comparable with that of whole mitochondria from these tissues. 4. Thyroidectomy results in increased half-lives of liver and kidney mitochondria, with no apparent change in the half-life of brain mitochondria. 5. A detailed investigation of the turnover rates of several protein components revealed a significant decrease in the turnover rates of mitochondrial insoluble proteins from the three tissues under study. 6. The turnover rates of m-DNA of liver and kidney show a parallel decrease. 7. Thus it is apparent that thyroid hormone(s) may have a regulatory role in maintaining the synchrony of turnover of liver and kidney mitochondria in the euthyroid state. Turnover of brain mitochondria may perhaps be regulated by some other factor(s) in addition to thyroid hormone(s). 8. It seems likely that during mitochondrial turnover m-DNA and insoluble proteins may constitute a major unit. 9. The mitochondrial protein contents of the three tissues are not affected by thyroidectomy. 10. No correlation was seen between the turnover rate of mitochondria and cathepsin activity in any of the tissues under study in normal or thyroidectomized animals. 11. On the other hand, mitochondrial proteinase activity shows good correlation with the turnover rates of mitochondria in normal animals, and a parallel decrease in activity comparable with the decreased rates of turnover is observed after thyroidectomy. 12. It is concluded that mitochondrial proteinase activity may play a significant role in their protein turnover.

scholarly journals Generation of a Mitochondrial Protein Compendium in Dictyostelium Discoideum

2021 ◽  
Author(s):  
Anna V Freitas ◽  
Jake T Herb ◽  
Miao Pan ◽  
Yong Cheng ◽  
Marjan Gucek ◽  
...  
Keyword(s):  
Dictyostelium Discoideum ◽  
Mitochondrial Protein ◽  
Metabolic Reprogramming ◽  
Mitochondrial Proteins ◽  
Mitochondrial Proteome ◽  
Cellular Processes ◽  
Proteomic Approach ◽  
The Social ◽  
Cellular Pathways ◽  
Alpha Proteobacteria

Abstract The social amoeba Dictyostelium discoideum is a well-established model to study numerous cellular processes including cell motility, chemotaxis, and differentiation. As energy metabolism is involved in these processes, mitochondrial genetics and bioenergetics are of interest, though many features of Dictyostelium mitochondria differ from metazoans. A comprehensive inventory of mitochondrial proteins is critical to understanding mitochondrial processes and their involvement in various cellular pathways. Here, we utilized high-throughput multiplexed protein quantitation and homology analyses to generate a high-confidence mitochondrial protein compendium. Our proteomic approach, which utilizes quantitative mass spectrometry in combination with mathematical modeling, was validated through mitochondrial targeting sequence prediction and live-cell imaging. Our final compendium consists of 1082 proteins. Within our D. discoideum mitochondrial proteome, we identify many proteins that are not present in humans, yeasts, or the ancestral alpha-proteobacteria, which can serve as a foundation for future investigations into the unique mitochondria of Dictyostelium. Additionally, we leverage our compendium to highlight the complexity of metabolic reprogramming during starvation-induced development. Our compendium lays a foundation to investigate mitochondrial processes that are unique in protists, as well as for future studies to understand the functions of conserved mitochondrial proteins in health and diseases using D. discoideum as the model.

scholarly journals Mitochondrial protein turnover: Methods to measure turnover rates on a large scale

2015 ◽  
Vol 78 ◽  
pp. 54-61 ◽  
Author(s):  
X’avia C.Y. Chan ◽  
Caitlin M. Black ◽  
Amanda J. Lin ◽  
Peipei Ping ◽  
Edward Lau
Keyword(s):  
Protein Turnover ◽  
Large Scale ◽  
Mitochondrial Protein ◽  
Turnover Rates

scholarly journals Influence of Subcellular Localization and Functional State on Protein Turnover

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1747
Author(s):  
Roya Yousefi ◽  
Kristina Jevdokimenko ◽  
Verena Kluever ◽  
David Pacheu-Grau ◽  
Eugenio F. Fornasiero
Keyword(s):  
Subcellular Localization ◽  
Functional State ◽  
Protein Turnover ◽  
Protein Localization ◽  
Small Gtpase ◽  
Turnover Rates ◽  
Cellular Behavior ◽  
Two Factors ◽  
Brain Creatine Kinase ◽  
Selection Of

Protein homeostasis is an equilibrium of paramount importance that maintains cellular performance by preserving an efficient proteome. This equilibrium avoids the accumulation of potentially toxic proteins, which could lead to cellular stress and death. While the regulators of proteostasis are the machineries controlling protein production, folding and degradation, several other factors can influence this process. Here, we have considered two factors influencing protein turnover: the subcellular localization of a protein and its functional state. For this purpose, we used an imaging approach based on the pulse-labeling of 17 representative SNAP-tag constructs for measuring protein lifetimes. With this approach, we obtained precise measurements of protein turnover rates in several subcellular compartments. We also tested a selection of mutants modulating the function of three extensively studied proteins, the Ca2+ sensor calmodulin, the small GTPase Rab5a and the brain creatine kinase (CKB). Finally, we followed up on the increased lifetime observed for the constitutively active Rab5a (Q79L), and we found that its stabilization correlates with enlarged endosomes and increased interaction with membranes. Overall, our data reveal that both changes in protein localization and functional state are key modulators of protein turnover, and protein lifetime fluctuations can be considered to infer changes in cellular behavior.

scholarly journals Characterization of Mmp37p, aSaccharomyces cerevisiaeMitochondrial Matrix Protein with a Role in Mitochondrial Protein Import

2006 ◽  
Vol 17 (9) ◽  
pp. 4051-4062 ◽  
Author(s):  
Michelle R. Gallas ◽  
Mary K. Dienhart ◽  
Rosemary A. Stuart ◽  
Roy M. Long
Keyword(s):  
Matrix Protein ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Temperature Sensitive ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane ◽  
Close Proximity ◽  
The Matrix ◽  
Targeting Signal

Many mitochondrial proteins are encoded by nuclear genes and after translation in the cytoplasm are imported via translocases in the outer and inner membranes, the TOM and TIM complexes, respectively. Here, we report the characterization of the mitochondrial protein, Mmp37p (YGR046w) and demonstrate its involvement in the process of protein import into mitochondria. Haploid cells deleted of MMP37 are viable but display a temperature-sensitive growth phenotype and are inviable in the absence of mitochondrial DNA. Mmp37p is located in the mitochondrial matrix where it is peripherally associated with the inner membrane. We show that Mmp37p has a role in the translocation of proteins across the mitochondrial inner membrane via the TIM23-PAM complex and further demonstrate that substrates containing a tightly folded domain in close proximity to their mitochondrial targeting sequences display a particular dependency on Mmp37p for mitochondrial import. Prior unfolding of the preprotein, or extension of the region between the targeting signal and the tightly folded domain, relieves their dependency for Mmp37p. Furthermore, evidence is presented to show that Mmp37 may affect the assembly state of the TIM23 complex. On the basis of these findings, we hypothesize that the presence of Mmp37p enhances the early stages of the TIM23 matrix import pathway to ensure engagement of incoming preproteins with the mtHsp70p/PAM complex, a step that is necessary to drive the unfolding and complete translocation of the preprotein into the matrix.

scholarly journals Insertion Defects of Mitochondrially Encoded Proteins Burden the Mitochondrial Quality Control System

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 172 ◽  
Author(s):  
Braulio Vargas Möller-Hergt ◽  
Andreas Carlström ◽  
Tamara Suhm ◽  
Martin Ott
Keyword(s):  
Quality Control ◽  
Control System ◽  
Mitochondrial Protein ◽  
Quality Control System ◽  
Yeast Cells ◽  
Mitochondrial Quality Control ◽  
Protein Insertion ◽  
Mitochondrial Proteome ◽  
Proteotoxic Stress ◽  
Membrane Protein Insertion

The mitochondrial proteome contains proteins from two different genetic systems. Proteins are either synthesized in the cytosol and imported into the different compartments of the organelle or directly produced in the mitochondrial matrix. To ensure proteostasis, proteins are monitored by the mitochondrial quality control system, which will degrade non-native polypeptides. Defective mitochondrial membrane proteins are degraded by membrane-bound AAA-proteases. These proteases are regulated by factors promoting protein turnover or preventing their degradation. Here we determined genetic interactions between the mitoribosome receptors Mrx15 and Mba1 with the quality control system. We show that simultaneous absence of Mrx15 and the regulators of the i-AAA protease Mgr1 and Mgr3 provokes respiratory deficiency. Surprisingly, mutants lacking Mrx15 were more tolerant against proteotoxic stress. Furthermore, yeast cells became hypersensitive against proteotoxic stress upon deletion of MBA1. Contrary to Mrx15, Mba1 cooperates with the regulators of the m-AAA and i-AAA proteases. Taken together, these results suggest that membrane protein insertion and mitochondrial AAA-proteases are functionally coupled, possibly reflecting an early quality control step during mitochondrial protein synthesis.

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