scholarly journals Increased supraorganization of respiratory complexes is a dynamic multistep remodelling in response to proteostasis stress

2020 ◽  
Vol 133 (18) ◽  
pp. jcs248492
Author(s):  
Shivali Rawat ◽  
Suparna Ghosh ◽  
Debodyuti Mondal ◽  
Valpadashi Anusha ◽  
Swasti Raychaudhuri
Keyword(s):  
Complex I ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Complex Iii ◽  
Complex Iv ◽  
Mitochondrial Proteome ◽  
Respiratory Complexes ◽  
The Core ◽  
Mitochondrial Functions ◽  
Folding Pathways

ABSTRACTProteasome-mediated degradation of misfolded proteins prevents aggregation inside and outside mitochondria. But how do cells safeguard the mitochondrial proteome and mitochondrial functions despite increased aggregation during proteasome inactivation? Here, using a novel two-dimensional complexome profiling strategy, we report increased supraorganization of respiratory complexes (RCs) in proteasome-inhibited cells that occurs simultaneously with increased pelletable aggregation of RC subunits inside mitochondria. Complex II (CII) and complex V (CV) subunits are increasingly incorporated into oligomers. Complex I (CI), complex III (CIII) and complex IV (CIV) subunits are engaged in supercomplex formation. We unravel unique quinary states of supercomplexes during early proteostatic stress that exhibit plasticity and inequivalence of constituent RCs. The core stoichiometry of CI and CIII is preserved, whereas the composition of CIV varies. These partially disintegrated supercomplexes remain functionally competent via conformational optimization. Subsequently, increased stepwise integration of RC subunits into holocomplexes and supercomplexes re-establishes steady-state stoichiometry. Overall, the mechanism of increased supraorganization of RCs mimics the cooperative unfolding and folding pathways for protein folding, but is restricted to RCs and is not observed for any other mitochondrial protein complexes.This article has an associated First Person interview with the first author of the paper.

scholarly journals Mitochondrial Function and Parkinson’s Disease: From the Perspective of the Electron Transport Chain

2021 ◽  
Vol 14 ◽  
Author(s):  
Jeng-Lin Li ◽  
Tai-Yi Lin ◽  
Po-Lin Chen ◽  
Ting-Ni Guo ◽  
Shu-Yi Huang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Direct Evidence ◽  
Complex Iii ◽  
Complex Iv ◽  
Transport Chain ◽  
Mitochondrial Functions

Parkinson’s disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

scholarly journals Aging of Podospora anserina Leads to Alterations of OXPHOS and the Induction of Non-Mitochondrial Salvage Pathways

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3319
Author(s):  
Verena Warnsmann ◽  
Jana Meisterknecht ◽  
Ilka Wittig ◽  
Heinz D. Osiewacz
Keyword(s):  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Podospora Anserina ◽  
Mitochondrial Morphology ◽  
Complex Iv ◽  
Protein Levels ◽  
Age Dependent ◽  
Functionally Impaired ◽  
Salvage Pathways

The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.

scholarly journals Maize pentatricopeptide repeat protein DEK53 is required for mitochondrial RNA editing at multiple sites and seed development

2020 ◽  
Vol 71 (20) ◽  
pp. 6246-6261 ◽  
Author(s):  
Dawei Dai ◽  
Lifang Jin ◽  
Zhenzhen Huo ◽  
Shumei Yan ◽  
Zeyang Ma ◽  
...  
Keyword(s):  
Rna Editing ◽  
Protein Complexes ◽  
Plant Mitochondria ◽  
Mitochondrial Protein ◽  
Electron Microscopic Examination ◽  
Complex Iii ◽  
Mitochondrial Rna ◽  
Pentatricopeptide Repeat ◽  
Electron Microscopic ◽  
Ppr Protein

Abstract Pentatricopeptide repeat (PPR) proteins were identified as site-specific recognition factors for RNA editing in plant mitochondria and plastids. In this study, we characterized maize (Zea mays) kernel mutant defective kernel 53 (dek53), which has an embryo lethal and collapsed endosperm phenotype. Dek53 encodes an E-subgroup PPR protein, which possesses a short PLS repeat region of only seven repeats. Subcellular localization analysis indicated that DEK53 is localized in the mitochondrion. Strand- and transcript-specific RNA-seq analysis showed that the dek53 mutation affected C-to-U RNA editing at more than 60 mitochondrial C targets. Biochemical analysis of mitochondrial protein complexes revealed a significant reduction in the assembly of mitochondrial complex III in dek53. Transmission electron microscopic examination showed severe morphological defects of mitochondria in dek53 endosperm cells. In addition, yeast two-hybrid and luciferase complementation imaging assays indicated that DEK53 can interact with the mitochondrion-targeted non-PPR RNA editing factor ZmMORF1, suggesting that DEK53 might be a functional component of the organellar RNA editosome.

scholarly journals MITOCHONDRIAL PROTEIN PROFILE AND ITS ROLE IN PATHOLOGIC PROCESSES

2013 ◽  
Vol 12 (3) ◽  
pp. 5-17
Author(s):  
Ye. A. Kosterina ◽  
I. I. Kozenkov ◽  
V. A. Kasymov ◽  
P. A. Kamensky ◽  
I. N. Dominova ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Profile ◽  
Mitochondrial Protein ◽  
Proteome Profiling ◽  
Mitochondrial Proteome ◽  
Mitochondrial Functions ◽  
Precursor Proteins ◽  
Real Size ◽  
Pathologic Processes

Mitochondria import hundreds of different precursor proteins from the cytosol, and only 13 proteins are encoded by mtDNA itself. Recent investigations demonstrated real size of mitochondrial proteome and complexity of their functions There are many methods using for mitochondrial proteome profiling, that help to understand a molecular mechanisms of mitochondrial functions and identify the causes of disruptions that lead to different disorders. In this review we discuss a recent data in the field of mitochondrial proteomics.

scholarly journals Hypoxia Promotes Mitochondrial Complex I Abundance via HIF-1α in Complex III and Complex IV Deficient Cells

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2197
Author(s):  
Amy Saldana-Caboverde ◽  
Nadee Nissanka ◽  
Sofia Garcia ◽  
Anne Lombès ◽  
Francisca Diaz
Keyword(s):  
Complex I ◽  
De Novo ◽  
Genetic Defect ◽  
Pleiotropic Effect ◽  
Complex Iii ◽  
Low Oxygen ◽  
Respiratory Complexes ◽  
Hypoxia Exposure ◽  
Hypoxic Conditions ◽  
Rieske Iron Sulfur Protein

Murine fibroblasts deficient in mitochondria respiratory complexes III (CIII) and IV (CIV) produced by either the ablation of Uqcrfs1 (encoding for Rieske iron sulfur protein, RISP) or Cox10 (encoding for protoheme IX farnesyltransferase, COX10) genes, respectively, showed a pleiotropic effect in complex I (CI). Exposure to 1–5% oxygen increased the levels of CI in both RISP and COX10 KO fibroblasts. De novo assembly of the respiratory complexes occurred at a faster rate and to higher levels in 1% oxygen compared to normoxia in both RISP and COX10 KO fibroblasts. Hypoxia did not affect the levels of assembly of CIII in the COX10 KO fibroblasts nor abrogated the genetic defect impairing CIV assembly. Mitochondrial signaling involving reactive oxygen species (ROS) has been implicated as necessary for HIF-1α stabilization in hypoxia. We did not observe increased ROS production in hypoxia. Exposure to low oxygen levels stabilized HIF-1α and increased CI levels in RISP and COX10 KO fibroblasts. Knockdown of HIF-1α during hypoxic conditions abrogated the beneficial effect of hypoxia on the stability/assembly of CI. These findings demonstrate that oxygen and HIF-1α regulate the assembly of respiratory complexes.

scholarly journals Integrated Multi-Omic Data Analysis and Validation with Yeast Model Show Oxidative Phosphorylation Modulate Protein Aggregation in Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Sai Swaroop ◽  
Akhil PS ◽  
Sai Sanwid Pradhan ◽  
Bandana Prasad ◽  
Raksha Rao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Oxidative Phosphorylation ◽  
Complex I ◽  
Critical Role ◽  
Complex Iii ◽  
Integrative Approach ◽  
Complex Iv ◽  
Knock Out ◽  
Lateral Sclerosis ◽  
Yeast Model

Abstract Amyotrophic Lateral Sclerosis is a progressive, incurable amyloid aggregating neurodegenerative disease involving the motor neurons. Identification of potential biomarkers and therapeutic targets can assist in the better management of the disease. We used an integrative approach encompassing analysis of transcriptomic datasets of human and mice from GEO database. Our analysis of ALS patient datasets showed deregulation in Non-alcoholic fatty acid liver disease and oxidative phosphorylation. Transgenic mice datasets pertaining to SOD1, FUS and TDP-43 showed deregulation in oxidative phosphorylation and ribosome associated pathways. Commonality analysis between the human and mice datasets showed oxidative phosphorylation as a major deregulated pathway among the different datasets. Further, gene expression analysis of mitochondrial electron transport chain show downregulation of genes belonging to Complex I and IV. The results were then validated using the yeast model system. Inhibitor studies using metformin (complex-I inhibitor) and malonate (complex-II inhibitor) did not have any effect in mitigating the amyloids while antimycin (complex-III inhibitor) and azide (complex-IV inhibitor) reduced amyloidogenesis. Knock-out of QCR8 (complex-III) or COX8 (complex–IV) completely cleared the amyloids. Taken together, our results show a critical role for mitochondrial oxidative phosphorylation in amyloidogenesis and as a potential therapeutic target in ALS.

scholarly journals Functional asymmetry and electron flow in the bovine respirasome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Joana S Sousa ◽  
Deryck J Mills ◽  
Janet Vonck ◽  
Werner Kühlbrandt
Keyword(s):  
Complex I ◽  
Electron Flow ◽  
Functional Asymmetry ◽  
Complex Iii ◽  
Central Position ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Chain Complexes ◽  
Complex Iv ◽  
Iron Sulfur Cluster ◽  
Active Complex

Respirasomes are macromolecular assemblies of the respiratory chain complexes I, III and IV in the inner mitochondrial membrane. We determined the structure of supercomplex I1III2IV1 from bovine heart mitochondria by cryo-EM at 9 Å resolution. Most protein-protein contacts between complex I, III and IV in the membrane are mediated by supernumerary subunits. Of the two Rieske iron-sulfur cluster domains in the complex III dimer, one is resolved, indicating that this domain is immobile and unable to transfer electrons. The central position of the active complex III monomer between complex I and IV in the respirasome is optimal for accepting reduced quinone from complex I over a short diffusion distance of 11 nm, and delivering reduced cytochrome c to complex IV. The functional asymmetry of complex III provides strong evidence for directed electron flow from complex I to complex IV through the active complex III monomer in the mammalian supercomplex.

scholarly journals Protein Interaction Patterns in Arabidopsis thaliana Leaf Mitochondria Change in Response to Illumination

2020 ◽  
Author(s):  
Nils Rugen ◽  
Frank Schaarschmidt ◽  
Hans-Peter Braun ◽  
Holger Eubel
Keyword(s):  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Tca Cycle ◽  
Mass Range ◽  
Cellular Respiration ◽  
Interaction Patterns ◽  
Large Protein ◽  
The Tca Cycle ◽  
Mitochondrial Functions

Mitochondrial biology is underpinned by the presence and activity of large protein complexes participating in the organelle-located parts of cellular respiration, the TCA cycle and oxidative phosphorylation. While the enzymatic roles of these complexes are undisputed, little is known about the interactions of the subunits beyond their presence in the monomeric protein complexes and their functions in regulating mitochondria metabolism. By applying one of the most important regulatory cues for plant metabolism, the presence or absence of light, we here assess the changes in the composition and molecular mass of known mitochondrial protein complexes by employing a differential complexome profiling strategy. Covering a mass range up to 25 MDa, we demonstrate dynamic associations of TCA-cycle enzymes and of OXPHOS components. The data presented here form the basis for future studies aiming to advance our understanding of the role of protein:protein interactions in the regulation of plant mitochondrial functions.

scholarly journals A high-density human mitochondrial proximity interaction network

2020 ◽  
Author(s):  
Hana Antonicka ◽  
Zhen-Yuan Lin ◽  
Alexandre Janer ◽  
Woranontee Weraarpachai ◽  
Anne-Claude Gingras ◽  
...  
Keyword(s):  
High Resolution ◽  
Correlation Analysis ◽  
Mitochondrial Protein ◽  
Interaction Network ◽  
Mitochondrial Proteins ◽  
Site Formation ◽  
List Type ◽  
Mitochondrial Proteome ◽  
Mitochondrial Functions ◽  
The Matrix

SummaryWe used BioID, a proximity-dependent biotinylation assay, to interrogate 100 mitochondrial baits from all mitochondrial sub-compartments to create a high resolution human mitochondrial proximity interaction network. We identified 1465 proteins, producing 15626 unique high confidence proximity interactions. Of these, 528 proteins were previously annotated as mitochondrial, nearly half of the mitochondrial proteome defined by Mitocarta 2.0. Bait-bait analysis showed a clear separation of mitochondrial compartments, and correlation analysis among preys across all baits allowed us to identify functional clusters involved in diverse mitochondrial functions, and to assign uncharacterized proteins to specific modules. We demonstrate that this analysis can assign isoforms of the same mitochondrial protein to different mitochondrial sub-compartments, and show that some proteins may have multiple cellular locations. Outer membrane baits showed specific proximity interactions with cytosolic proteins and proteins in other organellar membranes, suggesting specialization of proteins responsible for contact site formation between mitochondria and individual organelles. This proximity network will be a valuable resource for exploring the biology of uncharacterized mitochondrial proteins, the interactions of mitochondria with other cellular organelles, and will provide a framework to interpret alterations in sub-mitochondrial environments associated with mitochondrial disease.Bullet pointsWe created a high resolution human mitochondrial protein proximity map using BioIDBait-bait analysis showed that the map has sub-compartment resolution and correlation analysis of preys identified functional clusters and assigned proteins to specific modulesWe identified isoforms of matrix and IMS proteins with multiple cellular localizations and an endonuclease that localizes to both the matrix and the OMMOMM baits showed specific interactions with non-mitochondrial proteins reflecting organellar contact sites and protein dual localization

scholarly journals Conserved in situ arrangement of complex I and III2 in mitochondrial respiratory chain supercomplexes of mammals, yeast, and plants

2018 ◽  
Vol 115 (12) ◽  
pp. 3024-3029 ◽  
Author(s):  
Karen M. Davies ◽  
Thorsten B. Blum ◽  
Werner Kühlbrandt
Keyword(s):  
Respiratory Chain ◽  
Complex I ◽  
Principal Component ◽  
Complex Iii ◽  
Asparagus Officinalis ◽  
Mutual Arrangement ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Chain Complexes ◽  
Complex Iv

We used electron cryo-tomography and subtomogram averaging to investigate the structure of complex I and its supramolecular assemblies in the inner mitochondrial membrane of mammals, fungi, and plants. Tomographic volumes containing complex I were averaged at ∼4 nm resolution. Principal component analysis indicated that ∼60% of complex I formed a supercomplex with dimeric complex III, while ∼40% were not associated with other respiratory chain complexes. The mutual arrangement of complex I and III2 was essentially conserved in all supercomplexes investigated. In addition, up to two copies of monomeric complex IV were associated with the complex I1III2 assembly in bovine heart and the yeast Yarrowia lipolytica, but their positions varied. No complex IV was detected in the respiratory supercomplex of the plant Asparagus officinalis. Instead, an ∼4.5-nm globular protein density was observed on the matrix side of the complex I membrane arm, which we assign to γ-carbonic anhydrase. Our results demonstrate that respiratory chain supercomplexes in situ have a conserved core of complex I and III2, but otherwise their stoichiometry and structure varies. The conserved features of supercomplex assemblies indicate an important role in respiratory electron transfer.

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