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

Abstract MP252: Genetic Architecture Of Heart Mitochondrial Proteome Influencing Cardiac Hypertrophy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Karthickeyan Chella Krishnan ◽  
Elie-Julien El Hachem ◽  
Christine Light ◽  
Varun Shravah ◽  
Diana Anum ◽  
...  
Keyword(s):  
High Resolution ◽  
Ribosomal Proteins ◽  
Heart Function ◽  
Mitochondrial Protein ◽  
Strong Support ◽  
Mitochondrial Proteins ◽  
Heart Hypertrophy ◽  
Genetic Loci ◽  
Mouse Population ◽  
Mitochondrial Proteome

Our lab studies how natural genetic variations affect common diseases using a mouse population called hybrid mouse diversity panel (HMDP). In this study, we have explored the genetic regulation of mitochondrial pathways and their contribution to heart function using an integrative proteomics approach. We first performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and surveyed mitochondrial localization using MitoCarta2.0. We retrieved 840 of these proteins (quantified in ≥50 strains) and performed high-resolution association mapping on their respective abundance levels to the HMDP genotypes. Our analyses identified three genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively. All three are associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. Next, to identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA) and identified five modules. Eigengenes, representing the first principal component of two of these modules (Brown and Green), mapped to the same regions as the chr13 and chr17 loci, respectively. DAVID enrichment analyses revealed that the Brown module (72 proteins, 96% overlap with chr13) was highly enriched for complex-I proteins (35 proteins, P = 8.8E-74) and the Green module (44 proteins, 73% overlap with chr17) for mitochondrial ribosomal proteins (25 proteins, P = 1.3E-53). The proteins in the chr7 locus were found primarily in the Turquoise module (393 proteins, 81% overlap) but this module was not enriched for any single mitochondrial protein complex. In summary, we now report the identification of three genetic loci that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Our results provide strong support for a role of the mitochondrial proteome in heart pathophysiology.

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 Causes and consequences of mitochondrial proteome size-variation in animals

2019 ◽  
Author(s):  
Viraj Muthye ◽  
Dennis Lavrov
Keyword(s):  
Functional Significance ◽  
Size Variation ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Factors Affecting ◽  
Mitochondrial Proteome ◽  
Mitochondrial Functions ◽  
Size Evolution ◽  
Targeting Signals ◽  
Gain And Loss

AbstractDespite a conserved set of core mitochondrial functions, animal mitochondrial proteomes show a large variation in size. In this study, we analyzed the putative mechanisms behind and functional significance of this variation using experimentally-verified mt-proteomes of four bilaterian animals and two non-animal outgroups. We found that, of several factors affecting mitochondrial proteome size, evolution of novel mitochondrial proteins in mammals and loss of ancestral proteins in protostomes were the main contributors. Interestingly, gain and loss of conventional mitochondrial targeting signals was not a significant factor in the proteome size evolution.

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 A prioritized and validated resource of mitochondrial proteins in Plasmodium identifies leads to unique biology

2021 ◽  
Author(s):  
Selma L. van Esveld ◽  
Lisette Meerstein-Kessel ◽  
Cas Boshoven ◽  
Jochem F. Baaij ◽  
Konstantin Barylyuk ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Mitochondrial Protein ◽  
Gene Expression Profiles ◽  
Amino Acid Sequences ◽  
Mitochondrial Proteins ◽  
Predictive Score ◽  
Mitochondrial Localization ◽  
Mitochondrial Proteome ◽  
False Discovery ◽  
Single Mitochondrion

AbstractPlasmodium species have a single mitochondrion that is essential for their survival and has been successfully targeted by anti-malarial drugs. Most proteins are imported into this organelle and our picture of the Plasmodium mitochondrial proteome remains incomplete. Many data sources contain information about mitochondrial localization, including proteome and gene expression profiles, orthology to mitochondrial proteins from other species, co-evolutionary relationships, and amino acid sequences, each with different coverage and reliability. To obtain a comprehensive, prioritized list of Plasmodium falciparum mitochondrial proteins, we rigorously analyzed and integrated eight datasets using Bayesian statistics into a predictive score per protein for mitochondrial localization. At a corrected false discovery rate of 25%, we identified 295 proteins with a sensitivity of 65% and a specificity of 98%. They include proteins that have not been identified as mitochondrial in other eukaryotes but have characterized homologs in bacteria that are involved in metabolism or translation. Mitochondrial localization of seven Plasmodium berghei orthologs was confirmed by epitope labeling and co-localization with a mitochondrial marker protein. One of these belongs to a newly identified apicomplexan mitochondrial protein family that in P. falciparum has four members. With the experimentally validated mitochondrial proteins and the complete ranked P. falciparum proteome, which we have named PlasmoMitoCarta, we present a resource to study unique proteins of Plasmodium mitochondria.

Mitochondrial diseases caused by dysfunctional mitochondrial protein import

2018 ◽  
Vol 46 (5) ◽  
pp. 1225-1238 ◽  
Author(s):  
Thomas Daniel Jackson ◽  
Catherine Sarah Palmer ◽  
Diana Stojanovski
Keyword(s):  
Mitochondrial Disease ◽  
Genetic Disease ◽  
Molecular Basis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Mitochondrial Proteins ◽  
Eukaryotic Cells ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Proteome

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

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 Increased Mitochondrial Protein Levels and Bioenergetics in the Musculus Rectus Femoris of Wfs1-Deficient Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Margus Eimre ◽  
Kalju Paju ◽  
Nadežda Peet ◽  
Lumme Kadaja ◽  
Marian Tarrend ◽  
...  
Keyword(s):  
Citrate Synthase ◽  
Mitochondrial Protein ◽  
Rectus Femoris ◽  
Wolfram Syndrome ◽  
Mitochondrial Proteins ◽  
Proton Leak ◽  
Mrna Levels ◽  
Plasma Insulin Concentration ◽  
Mitochondrial Functions ◽  
Deficient Mice

Wfs1 deficiency leads to a progressive loss of plasma insulin concentration, which should reduce the consumption of glucose in insulin-dependent tissues, causing a variety of changes in intracellular energy metabolism. Our objective here was to assess the changes in the amount and function of mitochondrial proteins in different muscles of Wfs1-deficient mice. Mitochondrial functions were assayed by high-resolution oxygraphy of permeabilized muscle fibers; the protein amount was evaluated by liquid chromatography tandem mass spectrometry (LC/MS/MS) analysis and mRNA levels of the uncoupler proteins UCP2 and UCP3 by real-time PCR; and citrate synthase (CS) activity was determined spectrophotometrically in muscle homogenates. Compared to controls, there were no changes in proton leak and citrate synthase activity in the heart and m. soleus tissues of Wfs1-deficient mice, but significantly higher levels of both of these factors were observed in the m. rectus femoris; mitochondrial proteins and mRNA of UCP2 were also higher in the m. rectus femoris. ADP-stimulated state 3 respiration was lower in the m. soleus, remained unchanged in the heart, and was higher in the m. rectus femoris. The mitochondrial protein amount and activity are higher in Wfs1-deficient mice, as are mitochondrial proton leak and oxygen consumption in m. rectus femoris. These changes in muscle metabolism may be important for identifying the mechanisms responsible for Wolfram syndrome and diabetes.

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.

Mitochondrial Proteome from Human Peripheral Blood Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4193-4193
Author(s):  
Jean-Emmanuel Sarry ◽  
Gwenn-ael Danet-Desnoyers ◽  
Martin Carroll ◽  
Stephen G. Emerson ◽  
Fevzi Daldal ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Blood Cell ◽  
Succinate Dehydrogenase ◽  
Density Gradient ◽  
Peripheral Blood ◽  
Mitochondrial Protein ◽  
Red Cells ◽  
Mitochondrial Proteins ◽  
Cell Populations ◽  
Mitochondrial Proteome

Abstract Mitochondria play a special role in iron metabolism as the site of heme synthesis for hemoglobin. Mitochondria also function in cellular respiration, apoptosis, amino acid synthesis, Fe-S cluster formation and repair, and redox homeostasis; different blood cell lineages depend on some or all of these diverse mitochondrial functions. Mitochondrial abnormalities in hematopoietic stem cells might manifest themselves in proteomes of all the hematopoietic lineages. Therefore, we have begun characterization of mitochondria from different peripheral blood cell populations: platelets, lymphocytes, neutrophils and reticulocytes with the objective of comparing their function and proteomes in normals and in certain disease states. The procedures utilized as starting material a blood draw of approximately 80 ml from normal volunteers. The peripheral blood samples were separated by centrifugation and Hypaque density gradient into platelet, mononuclear cell, neutrophil and red cell populations. The red cells were further sorted by density gradient and magnetic cell sorting with specific CD71 microbeads to obtain enrichment of reticulocytes (reticulocytes retain their mitochondria and lose these upon maturation into mature red cells). The various cell fractions were evaluated by cell counting, flow cytometry and staining for morphology and identification. In accordance with differences in size and surface characteristics of these cell types, different procedures for cell rupture were utilized: shearing with a home-made device using ball bearings (mononuclear cells, neutrophils), nitrogen cavitation (platelets) and hypotonic shock (reticulocytes). Mitochondria were prepared by differential centrifugation and Percoll density gradient separation. The mitochondria were evaluated by fluorescence microscopy, flow cytometry, marker enzyme activity (succinate dehydrogenase) and Western blotting with compartment-specific antibodies. Mitochondrial protein profiles were obtained using 2-dimensional gel electrophoresis coupled to mass spectrometry. From 80 ml blood, 50 million lymphoctes were obtained equivalent to 150 microgram mitochondrial protein and 10 fold enrichment of succinate dehydrogenase activity. In parallel, K562 cell mitochondria were studied. The imaging analysis revealed significant differences in the protein patterns due to hematopoietic cell lineage. This work seeks to establish a proteomic database of shared and distinct erythroid, myeloid and lymphoid mitochondrial proteins that will form the basis of future studies of blood diseases in which perturbations of mitochondrial proteins are expected to occur. We are especially interested in examining the mitochondrial proteome and correlating with mitochondrial function in myelodysplasia and sideroblastic anemia.

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