Mitochondrial Reorganization Research Articles

Iron improves the antiviral activity of NK cells.

Natural killer (NK) cells are innate immune cells that play a crucial role as a first line of defense against viral infections and tumor development. Iron is an essential nutrient for immune cells, but it can also pose biochemical risks such as the production of reactive oxygen species. The importance of iron for the NK cell function has gained increasing recognition. We have previously shown that NK cells require iron to efficiently eliminate virus-infected target cells; however, the impact of nutritional iron deficiency on NK cell function and the therapeutic benefits of iron supplementation remain unclear. Here, we demonstrate that diet-related low iron levels lead to increased retroviral loads due to functional NK cell impairment, while iron supplementation enhances NK cell proliferation, as well as their cytotoxic efficacy. Notably, iron-treated NK cells exhibited significant metabolic changes, including mitochondrial reorganization. Interestingly, although iron supplementation decreased the NK cell's cytokine production, it significantly improved NK cell degranulation and the expression of cytotoxicity-associated proteins. These findings highlight the critical role of iron in maintaining NK cell immunity and suggest that iron supplementation may hold therapeutic potential for supporting the treatment of viral infections and immunodeficiency disorders.

Exercise-induced cardiac mitochondrial reorganization and enhancement in spontaneously hypertensive rats.

The myocardium is a highly oxidative tissue in which mitochondria are essential to supply the energy required to maintain pump function. When pathological hypertrophy develops, energy consumption augments and jeopardizes mitochondrial capacity. We explored the cardiac consequences of chronic swimming training, focusing on the mitochondrial network, in spontaneously hypertensive rats (SHR). Male adult SHR were randomized to sedentary or trained (T: 8-week swimming protocol). Blood pressure and echocardiograms were recorded, and hearts were removed at the end of the training period to perform molecular, imaging, or isolated mitochondria studies. Swimming improved cardiac midventricular shortening and decreased the pathological hypertrophic marker atrial natriuretic peptide. Oxidative stress was reduced, and even more interesting, mitochondrial spatial distribution, dynamics, function, and ATP were significantly improved in the myocardium of T rats. In the signaling pathway triggered by training, we detected an increase in the phosphorylation level of both AKT and glycogen synthase kinase-3 β, key downstream targets of insulin-like growth factor 1 signaling that are crucially involved in mitochondria biogenesis and integrity. Aerobic exercise training emerges as an effective approach to improve pathological cardiac hypertrophy and bioenergetics in hypertension-induced cardiac hypertrophy.

Protein Disulfide Isomerase overexpression induces mitochondrial reorganization and a differentiated VSMC phenotype: role of mitofusin-2

Protein Disulfide Isomerase overexpression induces mitochondrial reorganization and a differentiated VSMC phenotype: role of mitofusin-2

Mitochondrial Reorganization in Herpesvirus-Infected Cells.

Mitochondrial Reorganization in Herpesvirus-Infected Cells.

Pathology, epidemiology, and phylogeny of mussel egg disease due to the microsporidian Steinhausia mytilovum (Field, 1924) in the Mediterranean mussel (Mytilus galloprovincialis)

Microsporidia are well known fungal pathogens of aquatic animals. However, the taxonomy of microsporidia is generally poorly resolved, which has consequently constrained our understanding of their pathology and epidemiology in marine animals. To date, microsporidia have been reported in both bivalves and gastropods, and microsporidia from mollusks have been classified in different genera. Despite ongoing work to better describe these genera, including detailed microscopic and ultrastructural images, so far we lack information on microsporidian phylogeny and pathogenicity of species within these genera. Here we investigate the microsporidian parasite Steinhausia mytilovum associated with the mussel, Mytilus galloprovincialis, in natural beds and farms along coast of southern Italy. A survey of M. galloprovincialis was conducted in 13 mussel farms and one natural bed between 2009 and 2020. We found the presence of S. mytilovum in 10 of the investigated farms, with a prevalence ranging between 14 and 100% of female mussels, depending on the population and season in which they were sampled. The parasite developed in the oocytes within a sporophorous vesicle (SV) where it produced 1–3 spores per cell, both in the cytoplasm and in the nucleus. Stenhausia mytilovum elicited an infiltrative (24.8%) or a strong capsular inflammatory response (43.4%) at gonadal follicles and surrounding vesicular connective tissue, in some cases accompanied by gonadal atresia (24.8%), leading to loss of gonadal architecture. In 7% of cases no reaction was observed. Ultrastructural observations revealed a mitochondrial re-organization to interact with all the phases of parasite development; the mitochondria were arranged outside the parasitophorous vesicle (PV) or directly interacting with the spore inside vesicle. There are five taxonomic clades of microsporidians as identified by SSU ribosomal gene sequence data. Maximum likelihood analysis assigned S. mytilovum within the Clade IV, defined as the Class Terresporidia, with closest genetic relationship (83.6% identity) to an undetermined invertebrate ovarian microsporidian. The constant presence, prevalence, and severity of S. mytilovum in coastline populations of M. galloprovincialis populations in southern Italy may indirectly reflect immunocompetence at both individual and population levels.

Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.

Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (Cmax 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased 3H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6–3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24–48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease.

Sustained overexpression of Protein Disulfide Isomerase-A1 induces profound mitochondrial reorganization and a differentiated vascular smooth muscle phenotype

Sustained overexpression of Protein Disulfide Isomerase-A1 induces profound mitochondrial reorganization and a differentiated vascular smooth muscle phenotype

Improvement in mitochondrial oxidative phosphorylation of cardiomyocytes derived from human-induced pluripotent stem cells using micropatterned anisotropic substrates

Abstract Background/Introduction Alterations in cellular bioenergetic events owing to metabolic dysfunctions are well demonstrated in heart failure (HF). Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to model metabolic alterations as observed in the human failing hearts, which however requires precise arrangements of the respiratory chain complexes. Purpose Develop a method to improve the hiPSC-CMs architecture by using a micropatterned substrate (repeated lines of 30 μm-width separated with a cell repellant) that promotes elongation and anisotropy. Methods Cardiomyocyte differentiation was performed using a chemically defined method and 35 days later the generated hiPSC-CMs were cultured on unpatterned vs. micropatterned substrates for 7 additional days. Energy metabolic profiles were then measured using the Seahorse analyzer and mitochondrial components were analyzed by fluorescence microscopy and western blot. Results Cultures on micropatterned anisotropic substrates resulted in the generation of elongated cell morphology, rod-shaped hiPSC-CMs with improved sarcomere organization scores, and more aligned Z-lines. We first found a specific increase in oxidation phosphorylation (OXPHOS) activity in micropatterned CMs with a significant increase in the oxygen consumption rate (OCR) linked to basal respiration (58.4±24.0 vs 40.6±21.0 pmol/min, p<0.01), ATP production (49.6±19.1 vs 33.2±18.8 pmol/min, p<0.001) and maximal respiration (239.1±119.0 vs 123.0±68.5 pmol/min, p<0.001). Micropatterned CMs showed a better electron transport chain activity that explains the significantly decreased glycolytic function observed by Seahorse (17.2±9.9 vs 23.9±7.2 mpH/min, p<0.001). Micropatterned CMs displayed a more organized mitochondrial network, without evident change in mitochondrial mass. Transcriptomic profiling of micropatterned vs. unpatterned CMs revealed no significant differences. We next evaluated the proteomic profiling and found no significant change in the micropatterned CMs OXPHOS proteins expression. Conclusion(s) We developed a novel method for modeling metabolic activity in hiPSC-CMs based on micropatterned cultures. Our data show that the linear architectural pattern drives the formation and efficiency of OXPHOS function in cardiomyocytes with a mitochondrial structural reorganization. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence Nationale de la Recherche

Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.

ABSTRACTMale germline development involves choreographed changes to mitochondrial number, morphology and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.

Quantitative Phosphoproteomics Reveals Cell Alignment and Mitochondrial Length Change under Cyclic Stretching in Lung Cells.

Lung cancer is a leading cause of death. Most previous studies have been based on traditional cell-culturing methods. However, lung cells are periodically subjected to mechanical forces during breathing. Understanding the mechanisms underlying the cyclic stretching induced in lung cells may be important for lung cancer therapy. Here, we applied cyclic stretching to stimulate the continual contraction that is present under physiological conditions in lung cells. We first uncovered the stretching-induced phosphoproteome in lung cancer cell line A549 and fibroblast cell line IMR-90. We identified 2048 and 2604 phosphosites corresponding to 837 and 1008 phosphoproteins in A549 and IMR-90, respectively. Furthermore, we combined our phosphoproteomics and public gene expression data to identify the biological functions in response to cyclic stretching. Interestingly, cytoskeletal and mitochondrial reorganization were enriched. We further used cell imaging analysis to validate the profiling results and found that this physical force changed cell alignment and mitochondrial length. This study not only reveals the molecular mechanism of cyclic stretching but also provides evidence that cell stretching causes cellular rearrangement and mitochondrial length change.

Effect of environmental contamination on female and male gametes - A lesson from bovines.

Endocrine-disrupting compounds (EDCs) and foodborne contaminants are environmental pollutants that are considered reproductive toxicants due to their deleterious effects on female and male gametes. Among the EDCs, the phthalate plasticizers are of growing concern. In-vivo and in-vitro models indicate that the oocyte is highly sensitive to phthalates. This review summarizes the effects of di(2-ethylhexyl) phthalate and its major metabolite mono(2-ethyhexyl) phthalate (MEHP) on the oocyte. MEHP reduces the proportion of oocytes that fertilize, cleave and develop to the blastocyst stage. This is associated with negative effects on meiotic progression, and disruption of cortical granules, endoplasmic reticulum and mitochondrial reorganization. MEHP alters mitochondrial membrane polarity, increases reactive oxygen species levels and induces alterations in genes associated with oxidative phosphorylation. A carryover effect from the oocyte to the blastocyst is manifested by alterations in the transcriptomic profile of blastocysts developed from MEHP-treated oocytes. Among foodborne contaminants, the pesticide atrazine (ATZ) and the mycotoxin aflatoxin B1 (AFB1) are of high concern. The potential hazards associated with exposure of spermatozoa to these contaminants and their carryover effect to the blastocyst are described. AFB1 and ATZ reduce spermatozoa's viability, as reflected by a high proportion of cells with damaged plasma membrane; induce acrosome reaction, expressed as damage to the acrosomal membrane; and interfere with mitochondrial function, characterized by hyperpolarization of the membrane. ATZ and AFB1-treated spermatozoa show a high proportion of cells with fragmented DNA. Exposure of spermatozoa to AFB1 and ATZ reduces fertilization and cleavage rates, but not that of blastocyst formation. However, fertilization with AFB1- or ATZ-treated spermatozoa impairs transcript expression in the formed blastocysts, implying a carryover effect. Taken together, the review indicates the risk of exposing farm animals to environmental contaminants, and their deleterious effects on female and male gametes and the developing embryo.

A novel multicolor stimulated emission depletion (STED) microscopy strategy to visualize mitochondrial morphology in lymphocytes

Abstract Immunometabolism is an emerging field that studies the activation-induced reprogramming required to alter immune cell function and meet new energetic demands. In-depth investigations of the metabolism-related cellular changes necessitate high-resolution visualization of mitochondria. However, current strategies for imaging mitochondria are optimized for model cells with high cytoplasm-to-nucleus ratios and are not readily adaptable for many immune cells. Here, we devised a multicolor STED microscopy method to assess B lymphocyte mitochondria in resting and activated states. By staining specimens with TOM-20 and MitoTracker dyes, as well as DAPI and a viability dye, our strategy allowed us to assess the morphology and volumes of mitochondria while efficiently excluding dead cells. Our analyses showed that stimulation of B lymphocytes via toll-like receptor 9 (TLR9) and/or B cell receptor (BCR) led to notable mass and volume increases in individual mitochondria within 24 hours. Furthermore, TLR9-stimulated cells demonstrated more tubular and connected mitochondrial networks consistent with their higher metabolic demands. In addition, collecting images of the same specimens side-by-side on AiryScan and standard confocal laser microscopes showed that STED microscopy performed significantly better in resolving changes in 3D mitochondrial morphology. However, none of the light microscopy imaging strategies could resolve activation-induced structural alterations in cristae or mitochondrial matrix. In conclusion, our novel STED-based multicolor imaging approach offers a powerful super-resolution tool to study immunometabolism and mitochondrial reorganization in lymphocytes at the whole cell level.

Dispersed single wall carbon nanotubes do not impact mitochondria structure or function, but technical issues during analysis could yield incorrect results.

Mitochondria are the organelles of cells that generate a majority of the cell's energy through ATP and are involved in programmed cell death through apoptosis. An understanding of non-specific targeting of nanomaterials, including single wall carbon nanotubes (SWCNTs), to organelles is important in trying to modulate cell function or determine the cellular toxicity with long term exposure. Here, we examine the impact of SWCNTs dispersed with Pluronic F127 and protein on mitochondria using a battery of standard tests. Seahorse XF24 analysis suggests complete loss of mitochondiral function, but this data is artifactual due to SWCNTs adsorbing onto the Seahorse probes. Imaging using the mitochondrial functional dye JC-1 gives inconclusive results owing to fluorescence quenching by SWCNTs. We observe no co-localization or reorganization of mitochondria in the presence of SWCNTs, although the results could have been misinterpreted had we not been correcting for significant fluorescence quenching by SWCNTs. In sum, the surface activity and fluorescence quenching of SWCNTs alter many traditional cellular assays. However, light emitting (luciferase) assays show that ATP levels are not altered with SWCNT treatment suggesting that mitochondiral function is not impacted as well as that light-emitting assays are an essential complimentary approach for quantitative, unambiguous cellular study of nanomaterials.

Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming.

During the process of reprogramming to induced pluripotent stem (iPS) cells, somatic cells switch from oxidative to glycolytic metabolism, a transition associated with profound mitochondrial reorganization. Neither the importance of mitochondrial remodelling for cell reprogramming, nor the molecular mechanisms controlling this process are well understood. Here, we show that an early wave of mitochondrial fragmentation occurs upon expression of reprogramming factors. Reprogramming-induced mitochondrial fission is associated with a minor decrease in mitochondrial mass but not with mitophagy. The pro-fission factor Drp1 is phosphorylated early in reprogramming, and its knockdown and inhibition impairs both mitochondrial fragmentation and generation of iPS cell colonies. Drp1 phosphorylation depends on Erk activation in early reprogramming, which occurs, at least in part, due to downregulation of the MAP kinase phosphatase Dusp6. Taken together, our data indicate that mitochondrial fission controlled by an Erk-Drp1 axis constitutes an early and necessary step in the reprogramming process to pluripotency.

Oxygen tension and oocyte density during in vitro maturation affect the in vitro fertilization of bovine oocytes

<p>Oocyte maturation is the key factor affecting the fertilization and embryonic development. Factors such as oocyte density and oxygen tension can directly influence the IMV. Thus, the objective of this study was to evaluate the effect of the association of oxygen tensions (5% or 20%) with different oocyte densities (1:10?l or 1:20?l) in the <em>in vitro </em>maturation (IVM) of bovine oocytes on maturation and fertilization rates, ROS production and antioxidant activity. Three experiments were performed with bovine oocytes that were obtained from slaughterhouse ovaries. After selection, the oocytes were randomly distributed in four treatments: 1:10/5%; 1:10/20%; 1:20/5%and 1:20/20% for each experiment. In experiment I, nuclear maturation status and cytoplasmic maturation were evaluated through detection of the first polar body by immunofluorescence and the mitochondrial reorganization assay. In experiment II, ROS production and antioxidant activity were analyzed in oocytes and IVM medium after 24 h of maturation through detection of ROS, reduced glutathione (GSH) and Superoxide dismutase activity by spectrofluorimetric methods. In experiment III, fertilization was evaluated through pronucleus formation, sperm penetration with or without decondensation and polyspermy rates by immunofluorescence. In experiment I, the nuclear maturation and cytoplasmic maturation were similar among treatments (P>0.05). In experiment II, reactive oxygen species in oocytes were elevated in treatments with low oxygen tension which was independent of oocyte density (P<0.05). Additionally, ROS levels in IVM medium were higher in treatments with high oocyte density by volume of medium, which was independent of oxygen tension (P<0.05). In Experiment III, the fertilization and penetration rates were higher in the treatment with 20% oxygen tension and high oocyte density (P<0.05). Furthermore, a high incidence of polyspermy was observed in groups with high oxygen tension and low oocyte density (P<0.05). In conclusion, the results of this study indicate an interaction between oxygen tension and oocyte density, which increases ROS production in certain associations and subsequently influences the rates of <em>in vitro </em>fertilization of bovine oocytes. The improved rates of IVF were obtained when IVM was conducted using 20% oxygen tension and high oocyte density (1:20 ul).</p>

Oxygen tension and oocyte density during in vitro maturation affect the in vitro fertilization of bovine oocytes

Oocyte maturation is the key factor affecting the fertilization and embryonic development. Factors such as oocyte density and oxygen tension can directly influence the IMV. Thus, the objective of this study was to evaluate the effect of the association of oxygen tensions (5% or 20%) with different oocyte densities (1:10?l or 1:20?l) in the in vitro maturation (IVM) of bovine oocytes on maturation and fertilization rates, ROS production and antioxidant activity. Three experiments were performed with bovine oocytes that were obtained from slaughterhouse ovaries. After selection, the oocytes were randomly distributed in four treatments: 1:10/5%; 1:10/20%; 1:20/5%and 1:20/20% for each experiment. In experiment I, nuclear maturation status and cytoplasmic maturation were evaluated through detection of the first polar body by immunofluorescence and the mitochondrial reorganization assay. In experiment II, ROS production and antioxidant activity were analyzed in oocytes and IVM medium after 24 h of maturation through detection of ROS, reduced glutathione (GSH) and Superoxide dismutase activity by spectrofluorimetric methods. In experiment III, fertilization was evaluated through pronucleus formation, sperm penetration with or without decondensation and polyspermy rates by immunofluorescence. In experiment I, the nuclear maturation and cytoplasmic maturation were similar among treatments (P>0.05). In experiment II, reactive oxygen species in oocytes were elevated in treatments with low oxygen tension which was independent of oocyte density (P<0.05). Additionally, ROS levels in IVM medium were higher in treatments with high oocyte density by volume of medium, which was independent of oxygen tension (P<0.05). In Experiment III, the fertilization and penetration rates were higher in the treatment with 20% oxygen tension and high oocyte density (P<0.05). Furthermore, a high incidence of polyspermy was observed in groups with high oxygen tension and low oocyte density (P<0.05). In conclusion, the results of this study indicate an interaction between oxygen tension and oocyte density, which increases ROS production in certain associations and subsequently influences the rates of in vitro fertilization of bovine oocytes. The improved rates of IVF were obtained when IVM was conducted using 20% oxygen tension and high oocyte density (1:20 ul).

Prolonged starvation drives reversible sequestration of lipid biosynthetic enzymes and organelle reorganization in Saccharomyces cerevisiae.

Cells adapt to changing nutrient availability by modulating a variety of processes, including the spatial sequestration of enzymes, the physiological significance of which remains controversial. These enzyme deposits are claimed to represent aggregates of misfolded proteins, protein storage, or complexes with superior enzymatic activity. We monitored spatial distribution of lipid biosynthetic enzymes upon glucose depletion in Saccharomyces cerevisiae. Several different cytosolic-, endoplasmic reticulum-, and mitochondria-localized lipid biosynthetic enzymes sequester into distinct foci. Using the key enzyme fatty acid synthetase (FAS) as a model, we show that FAS foci represent active enzyme assemblies. Upon starvation, phospholipid synthesis remains active, although with some alterations, implying that other foci-forming lipid biosynthetic enzymes might retain activity as well. Thus sequestration may restrict enzymes' access to one another and their substrates, modulating metabolic flux. Enzyme sequestrations coincide with reversible drastic mitochondrial reorganization and concomitant loss of endoplasmic reticulum-mitochondria encounter structures and vacuole and mitochondria patch organelle contact sites that are reflected in qualitative and quantitative changes in phospholipid profiles. This highlights a novel mechanism that regulates lipid homeostasis without profoundly affecting the activity status of involved enzymes such that, upon entry into favorable growth conditions, cells can quickly alter lipid flux by relocalizing their enzymes.

Postnatal cardiomyocyte growth and mitochondrial reorganization cause multiple changes in the proteome of human cardiomyocytes

Fetal (fCM) and adult cardiomyocytes (aCM) significantly differ from each other both by structure and biochemical properties. aCM own a higher mitochondrial mass compared to fCM due to increased energy demand and show a greater density and higher degree of structural organization of myofibrils. The energy metabolism in aCM relies virtually completely on β-oxidation of fatty acids while fCM use carbohydrates. Rewinding of the aCM phenotype (de-differentiation) arises frequently in diseased hearts spurring questions about its functional relevance and the extent of de-differentiation. Yet, surprisingly little is known about the changes in the human proteome occurring during maturation of fCM to aCM. Here, we examined differences between human fetal and adult hearts resulting in the quantification of 3500 proteins. Moreover, we analyzed mitochondrial proteomes from both stages to obtain more detailed insight into underlying biochemical differences. We found that the majority of changes between fCM and aCM were attributed to growth and maturation of cardiomyocytes. As expected, adult hearts showed higher mitochondrial mass and expressed increased levels of proteins involved in energy metabolism but relatively lower copy numbers of mitochondrial DNA (mtDNA) per total cell volume. We uncovered that the TFAM/mtDNA ratio was kept constant during postnatal development despite a significant increase of mitochondrial protein per mtDNA in adult mitochondria, which revises previous concepts.

In This Issue

HomeCirculation ResearchVol. 111, No. 8In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Originally published28 Sep 2012https://doi.org/10.1161/RES.0b013e3182739a55Circulation Research. 2012;111:947Cy-3-G, Gut Flora, and RCT (p 967)Wang et al discover that microbes in the gut convey the atherosclerosis-busting benefits of a flavonoid found in fruit.Download figureDownload PowerPointIt is well known that red wine and fruits rich in color significantly lower the risk for atherosclerosis. This is, in large part due to their high levels of flavonoids, such as Cy-3-G. The maximum levels of this flavanoid detected in human blood, however, are far less than those necessary to reduce atherosclerotic risk. It is therefore thought that metabolites of Cy-3-G provide the main benefit—indeed, PCA, a known CY-3-G metabolite, has been shown to have anti-atherosclerotic effects. Wang et al have now discovered not only where PCA production happens in the body, but how it reduces atherosclerosis. While mice fed Cy-3-G produced high levels of plasma PCA, if given antibiotics, their plasma PCA levels were no longer detectable. If, however, these antibiotic-treated mice then had their gut microbes restored, their plasma PCA levels rebounded, confirming that gut microbes are essential for the production of PCA. In terms of mechanism, the team found that PCA reduced levels of miR-10b, a macrophage microRNA that suppresses cholesterol efflux-promoting proteins. More PCA thus induces more cholesterol efflux. The authors suggest that in addition to the manipulation of gut microbes, targeted repression of macrophage miR-10b might also be a viable treatment for atherosclerosis.Mitofusins in Early Postnatal Life (p 1012)In early postnatal development, reorganization of mitochondria in the heart is crucial for heart function, report Papanicolaou et al.Download figureDownload PowerPointWhen the circulatory system of a newborn mammal switches from placental to pulmonary oxygenation, the heart undergoes a series of dramatic changes. Myocytes not only cease to proliferate, undergo hypertrophy, and reorganize their cytoskeletons, but their mitochondria change shape, thicken, lose mobility and align with myofibrils and the sarcoplasmic reticulum. Papanicolaou et al have now discovered that mitofusin proteins can promote this remodeling of the postnatal heart, by regulating mitochondrial fusion, morphology, and dynamics. Mouse fetuses specifically engineered to lose Mitofusin 1 and 2 from their hearts at mid-gestation were as healthy as wild type fetuses, initially. But soon after birth, their hearts exhibited mitochondrial and structural abnormalities and the mice died approximately 1 to 2 weeks later. The engineered mice did actually develop large numbers of mitochondria but, unlike those of the wild type mice, they were spherical and either very large or very small. In wild type mice, the expression of Mitofusins 1 and 2 increased at birth, confirming the importance of these proteins in postnatal mitochondrial and cardiac function.GRK5 in Pathological Hypertrophy (p 1048)Inhibiting GRK5 kinase could slow down hypertrophy progression, suggest Gold et al.Download figureDownload PowerPointCardiac hypertrophy can be caused by, among other things, high blood pressure or post-infarction cardiac injury. And if these causal factors are not resolved, hypertrophy can ultimately lead to heart failure and eventual death. A significant pathological step in the progression of hypertrophy to heart failure is the increased expression of pro-hypertrophy genes. Gene regulators called histone deacetylases (HDACs) are known to repress such genes, but Gold et al previously found that over-expressing the kinase G protein-coupled receptor kinase 5 (GRK5) leads to the phosphorylation and inhibition of these HDACs. However, whether endogenous GRK5 could influence hypertrophy was unknown. Thus, Gold et al examined mice in which GRK5 had been genetically deleted—from the whole animal and from the heart tissue only. They found that both types of deletion significantly lessened the development of induced hypertrophy. Compared with their wild type counterparts, the genetically engineered mice showed reduced levels of phosphorylated HDACs and reduced expression of pro-hypertrophy genes. They also had smaller hearts and superior cardiac function. The authors conclude that inhibiting GRK5 activity in the heart could slow hypertrophy progression, thus reducing the risk of heart failure and death.Written by Ruth Williams Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mönch D, Koch J, Maaß A, Janssen N, Mürdter T, Renner P, Fallier-Becker P, Solaß W, Schwab M, Dahlke M, Schlitt H and Leibold T (2021) A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options , Pleura and Peritoneum, 10.1515/pp-2021-0128, 6:3, (121-129), Online publication date: 27-Sep-2021., Online publication date: 1-Sep-2021. September 28, 2012Vol 111, Issue 8 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/RES.0b013e3182739a55 Originally publishedSeptember 28, 2012 PDF download Advertisement