scholarly journals Proteomic analysis of the role of the quality control protease LONP1 in mitochondrial protein aggregation

2021 ◽  
Author(s):  
Karen Pollecker ◽  
Marc Sylvester ◽  
Wolfgang Voos
Keyword(s):  
Quality Control ◽  
Proteomic Analysis ◽  
Mitochondrial Protein ◽  
Model System ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Mild Phenotype ◽  
Ageing Processes ◽  
The Impact

AbstractThe mitochondrial matrix protease LONP1 is an essential part of the organellar protein quality control system. LONP1 has been shown to be involved in respiration control and apoptosis. Furthermore, a reduction in LONP1 level correlates with ageing processes. Up to now, the effects of a LONP1 defect were mostly studied by utilizing transient, siRNA-mediated knockdown approaches. We generated a new cellular model system for studying the impact of LONP1 on mitochondrial protein homeostasis by a CRISPR/Cas-mediated genetic knockdown (gKD). These cells show a stable reduction of LONP1 along with a mild phenotype characterized by absent morphological differences and only small negative effects on mitochondrial functions under normal culture conditions. To assess the consequences of a permanent LONP1 depletion on the mitochondrial proteome, we analyzed the alterations of protein levels by quantitative mass spectrometry, demonstrating small adaptive changes, in particular concerning mitochondrial protein biogenesis. In an additional proteomic analysis, we determined the temperature-dependent aggregation behavior of mitochondrial proteins and its dependence on a reduction of LONP1 activity, demonstrating the important role of the protease for mitochondrial protein homeostasis in mammalian cells. We identified a significant number of mitochondrial proteins that are affected by LONP1 activity concerning their stress-induced solubility. Taken together, our results suggest a very good applicability of the LONP1 gKD cell line as a model system for human ageing processes.

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

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

scholarly journals Mitochondrial microRNAs: A Putative Role in Tissue Regeneration

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 486
Author(s):  
Sílvia C. Rodrigues ◽  
Renato M. S. Cardoso ◽  
Filipe V. Duarte
Keyword(s):  
Tissue Regeneration ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Noncoding Rnas ◽  
Atp Synthesis ◽  
Mitochondrial Proteins ◽  
Cellular Mechanisms ◽  
Small Noncoding Rnas ◽  
Mitochondrial Ribosome

The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

scholarly journals MITOCHONDRIAL PROTEIN SYNTHESIS IN HELA CELLS

1974 ◽  
Vol 60 (3) ◽  
pp. 755-763 ◽  
Author(s):  
Jonas B. Galper
Keyword(s):  
Protein Synthesis ◽  
Ethidium Bromide ◽  
Mitochondrial Protein ◽  
Specific Protein ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Synthesis ◽  
Initiator Trna ◽  
Low Concentrations ◽  
Separate Protein

HeLa cell mitochondrial proteins have been shown to be the products of two separate protein-synthesizing systems; one, the general cellular mechanism, sensitive to inhibition by cycloheximide, the other, a specific mitochondrial system subject to inhibition by low concentrations of chloramphenicol (Galper, J. B., and J. E. Darnell. 1971. J. Mol. Biol 57:363). Preliminary data have suggested that a mitochondrial N-formyl-methionyl-tRNA (f-Met-tRNA) might be the initiator tRNA in the latter (Galper, J. B., and J. E. Darnell. 1969. Biochem. Biophys. Res. Commun. 34:205; 1971. J. Mol. Biol. 57:363). It is demonstrated here that the synthesis of these endogenous mitochondrial proteins is also subject to inhibition by ethidium bromide and decays with a half-life of 1½–2 h in cultures incubated with low concentrations of this dye. The role of formylated f-Met-tRNA as the initiator tRNA in the synthesis of mitochondrial proteins is supported by data from several experiments. The rates of ethidium bromide inhibition of both the charging of f-Met-tRNA and of the synthesis of mitochondrial proteins are strikingly similar. Inhibition by aminopterin of the formylation of f-Met-tRNA greatly depresses the rate of mitochondrial-specific protein synthesis. In the absence of the synthesis of these proteins, respiration, the levels of cytochromes a–a3 and b, and the number of mitochondrial cristae are decreased. The implications of these findings as they relate to mitochondrial biogenesis are discussed.

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 Chaperones and Proteases in Cardiomyocytes and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zee Chen ◽  
Lei Huang ◽  
Alexandria Tso ◽  
Shijia Wang ◽  
Xi Fang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nuclear Dna ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Oxygen Species ◽  
Mitochondrial Quality Control ◽  
The Matrix ◽  
Intracellular Ca ◽  
Mitochondrial Chaperones

Heart failure is one of the leading causes of morbidity and mortality worldwide. In cardiomyocytes, mitochondria are not only essential organelles providing more than 90% of the ATP necessary for contraction, but they also play critical roles in regulating intracellular Ca2+ signaling, lipid metabolism, production of reactive oxygen species (ROS), and apoptosis. Because mitochondrial DNA only encodes 13 proteins, most mitochondrial proteins are nuclear DNA-encoded, synthesized, and transported from the cytoplasm, refolded in the matrix to function alone or as a part of a complex, and degraded if damaged or incorrectly folded. Mitochondria possess a set of endogenous chaperones and proteases to maintain mitochondrial protein homeostasis. Perturbation of mitochondrial protein homeostasis usually precedes disruption of the whole mitochondrial quality control system and is recognized as one of the hallmarks of cardiomyocyte dysfunction and death. In this review, we focus on mitochondrial chaperones and proteases and summarize recent advances in understanding how these proteins are involved in the initiation and progression of heart failure.

scholarly journals Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

2021 ◽  
Author(s):  
Anna M. Schlagowski ◽  
Katharina Knöringer ◽  
Sandrine Morlot ◽  
Ana Sáchez Vicente ◽  
Felix Boos ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Model System ◽  
Model Systems ◽  
Aggregate Formation ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Polyq Protein ◽  
Rate Limiting

AbstractThe formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)

Sign in / Sign up

Export Citation Format

Share Document