Increased platelet mitochondrial function correlates with clot strength in a rodent fracture model.

Background: Thromboelastographic measures of clot strength increase early after injury, portending higher risks for thromboembolic complications during recovery. Understanding the specific role of platelets is challenging because of a lack of clinically relevant measures of platelet function. Platelet mitochondrial respirometry may provide insight to global platelet function but has not yet been correlated with functional coagulation studies.

Analysis of oxygen consumption rates in zebrafish reveals differences based on sex, age and physical activity recovery.

Mitochondrial dysfunction is linked to a variety of human diseases. Understanding the dynamic alterations in mitochondrial respiration at various stages of development is important to our understanding of disease progression. Zebrafish provide a system for investigating mitochondrial function and alterations during different life stages.

The cyclic lipopeptide micafungin induces rupture of isolated mitochondria by reprograming the mitochondrial inner membrane anion channel.

The antifungal activity of the drug micafungin, a cyclic lipopeptide that interacts with membrane proteins, may involve inhibition of fungal mitochondria. In humans, mitochondria are spared by the inability of micafungin to cross the cytoplasmic membrane. Using isolated mitochondria, we find that micafungin initiates the uptake of salts, causing rapid swelling and rupture of mitochondria with release of cytochrome c.

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition.

Background: Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium-glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT).

Angiotensin II type 1 receptor agonistic autoantibody blockade improves postpartum hypertension and cardiac mitochondrial function in rat model of preeclampsia.

Women with preeclampsia (PE) have a greater risk of developing hypertension, cardiovascular disease (CVD), and renal disease later in life. Angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE during pregnancy and up to 2-year postpartum (PP), and in the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of AT1-AA with a specific 7 amino acid peptide binding sequence ('n7AAc') improves pathophysiology observed in RUPP rats; however, the long-term effects of AT1-AA inhibition in PP is unknown.

Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV.

Hypoxia-inducible gene domain 1 (HIGD1) proteins are small integral membrane proteins, conserved from bacteria to humans, that associate with oxidative phosphorylation supercomplexes. Using yeast as a model organism, we have shown previously that its two HIGD1 proteins, Rcf1 and Rcf2, are required for the generation and maintenance of a normal membrane potential (ΔΨ) across the inner mitochondrial membrane (IMM). We postulated that the lower ΔΨ observed in the absence of the HIGD1 proteins may be due to decreased proton pumping by complex IV (CIV) or enhanced leak of protons across the IMM.

The yeast mitochondrial proteins Rcf1 and Rcf2 support the enzymology of the cytochrome oxidase complex and generation of the proton motive force.

The yeast mitochondrial proteins Rcf1 and Rcf2 are associated with a subpopulation of the cytochrome -cytochrome oxidase supercomplex and have been proposed to play a role in the assembly and/or modulation of the activity of the cytochrome oxidase (complex IV, CIV). Yeast mutants deficient in either Rcf1 or Rcf2 proteins can use aerobic respiration-based metabolism for growth, but the absence of both proteins results in a strong growth defect. In this study, using assorted biochemical and biophysical analyses of Rcf1/Rcf2 single and double null-mutant yeast cells and mitochondria, we further explored how Rcf1 and Rcf2 support aerobic respiration and growth.

Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion.

Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R).

The insertion of the non-heme Fe cofactor into nitric oxide reductase from P. denitrificans depends on NorQ and NorD accessory proteins.

Bacterial NO reductases (NOR) catalyze the reduction of NO into NO, either as a step in denitrification or as a detoxification mechanism. cNOR from Paracoccus (P.) denitrificans is expressed from the norCBQDEF operon, but only the NorB and NorC proteins are found in the purified NOR complex.

Structure of the alternative complex III in a supercomplex with cytochrome oxidase.

Alternative complex III (ACIII) is a key component of the respiratory and/or photosynthetic electron transport chains of many bacteria. Like complex III (also known as the bc complex), ACIII catalyses the oxidation of membrane-bound quinol and the reduction of cytochrome c or an equivalent electron carrier. However, the two complexes have no structural similarity.

WITHDRAWN: Characterization of the supercomplex formed by the alternative complex III and the terminal aa oxidase from Flavobacterium johnsoniae isolated in styrene:maleic acid copolymer nanodiscs.

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Mitochondrial cytochrome c oxidase biogenesis: Recent developments.

Mitochondrial cytochrome c oxidase (COX) is the primary site of cellular oxygen consumption and is essential for aerobic energy generation in the form of ATP. Human COX is a copper-heme A hetero-multimeric complex formed by 3 catalytic core subunits encoded in the mitochondrial DNA and 11 subunits encoded in the nuclear genome. Investigations over the last 50 years have progressively shed light into the sophistication surrounding COX biogenesis and the regulation of this process, disclosing multiple assembly factors, several redox-regulated processes leading to metal co-factor insertion, regulatory mechanisms to couple synthesis of COX subunits to COX assembly, and the incorporation of COX into respiratory supercomplexes.

Vertical sleeve gastrectomy improves indices of metabolic disease in rodent model of surgical menopause.

Objective: Although women are the most common recipients of weight loss surgeries for the amelioration of the comorbidities of obesity, few studies have addressed the efficacy of these procedures with specific attention to reproductive stage. Here we ask in a rodent model of vertical sleeve gastrectomy (VSG) whether improvements to metabolic health are realized in women having received surgical menopause. Specifically we were interested in knowing whether rats made menopausal through surgical means would exhibit persistent hepatic steatosis as reported in previously pregnant, freely cycling female VSG rats or if it is resolved as reported in male VSG rats.

Membrane-Anchored Cyclic Peptides as Effectors of Mitochondrial Oxidative Phosphorylation.

The echinocandins are membrane-anchored, cyclic lipopeptides (CLPs) with antifungal activity due to their ability to inhibit a glucan synthase located in the plasma membrane of fungi such as Candida albicans. A hydrophobic tail of an echinocandin CLP inserts into a membrane, placing a six-amino acid cyclic peptide near the membrane surface. Because processes critical for the function of the electron transfer complexes of mitochondria, such as proton uptake and release, take place near the surface of the membrane, we have tested the ability of two echinocandin CLPs, caspofungin and micafungin, to affect the activity of electron transfer complexes in isolated mammalian mitochondria.

Delipidation of cytochrome c oxidase from Rhodobacter sphaeroides destabilizes its quaternary structure.

Delipidation of detergent-solubilized cytochrome c oxidase isolated from Rhodobacter sphaeroides (Rbs-CcO) has no apparent structural and/or functional effect on the protein, however affects its resistance against thermal or chemical denaturation. Phospholipase A2 (PLA2) hydrolysis of phospholipids that are co-purified with the enzyme removes all but two tightly bound phosphatidylethanolamines. Replacement of the removed phospholipids with nonionic detergent decreases both thermal stability of the enzyme and its resilience against the effect of chemical denaturants such as urea.

Early alterations in platelet mitochondrial function are associated with survival and organ failure in patients with septic shock.

Introduction: The objective of the study is to determine if changes in platelet mitochondrial function in patients with sepsis are present early after presentation and the association of these changes with clinical outcomes and systemic metabolic function.

Materials And Methods: This is a prospective observational cohort study of a convenience sample of patients with severe sepsis. Mitochondrial function of intact, nonpermeabilized platelets suspended in their own plasma was estimated using high-resolution respirometry.

Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin.

We investigated obesity-induced changes in kidney lipid accumulation, mitochondrial function, and endoplasmic reticulum (ER) stress in the absence of hypertension, and the potential role of leptin in modulating these changes. We compared two normotensive genetic mouse models of obesity, leptin-deficient ob/ob mice and hyperleptinemic melanocortin-4 receptor-deficient mice (LoxTB MC4R-/-), with their respective lean controls. Compared with controls, ob/ob and LoxTB MC4R-/- mice exhibit significant albuminuria, increased creatinine clearance, and high renal triglyceride content.

Control of carotenoid biosynthesis through a heme-based cis-trans isomerase.

Plants synthesize carotenoids, which are essential for plant development and survival. These metabolites also serve as essential nutrients for human health. The biosynthetic pathway for all plant carotenoids occurs in chloroplasts and other plastids and requires 15-cis-ζ-carotene isomerase (Z-ISO).

Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability.

STAT3 has been implicated in mitochondrial function; however, the physiological relevance of this action is not established. Here we studied the importance of STAT3 to the cellular response to stimuli, TNFα and serum deprivation, which increase mitochondrial reactive oxygen species (ROS) formation. Experiments were performed using wild type (WT) and STAT3 knockout (KO) mouse embryonic fibroblasts (MEF).

Philosophy of voltage-gated proton channels.

In this review, voltage-gated proton channels are considered from a mainly teleological perspective. Why do proton channels exist? What good are they? Why did they go to such lengths to develop several unique hallmark properties such as extreme selectivity and ΔpH-dependent gating? Why is their current so minuscule? How do they manage to be so selective? What is the basis for our belief that they conduct H(+) and not OH(-)? Why do they exist in many species as dimers when the monomeric form seems to work quite well? It is hoped that pondering these questions will provide an introduction to these channels and a way to logically organize their peculiar properties as well as to understand how they are able to carry out some of their better-established biological functions.

Proton uptake and pKa changes in the uncoupled Asn139Cys variant of cytochrome c oxidase.

Cytochrome c oxidase (CytcO) is a membrane-bound enzyme that links electron transfer from cytochrome c to O(2) to proton pumping across the membrane. Protons are transferred through specific pathways that connect the protein surface with the catalytic site as well as the proton input with the proton output sides. Results from earlier studies have shown that one site within the so-called D proton pathway, Asn139, located ~10 Å from the protein surface, is particularly sensitive to mutations that uncouple the O(2) reduction reaction from the proton pumping activity.

Functional importance of a pair of conserved glutamic acid residues and of Ca(2+) binding in the cbb(3)-type oxygen reductases from Rhodobacter sphaeroides and Vibrio cholerae.

The cbb(3)-type cytochrome c oxidases are members of the family of heme-copper proton pumping respiratory oxygen reductases. The structure of the cbb(3)-type oxidase from Pseudomonas stutzeri reveals that, in addition to the six redox-active metal centers (two b-type hemes, three c-type hemes, and Cu(B)), the enzyme also contains at least one Ca(2+). The calcium bridges two propionate carboxyls at the interface between the low-spin heme b and the active-site heme b(3) and, in addition, is ligated to a serine in subunit CcoO and by a glutamate in subunit CcoN.

Evidence for a dual role of an active site histidine in α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase.

The previously reported crystal structures of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) show a five-coordinate Zn(II)(His)(3)(Asp)(OH(2)) active site. The water ligand is H-bonded to a conserved His228 residue adjacent to the metal center in ACMSD from Pseudomonas fluorescens (PfACMSD). Site-directed mutagenesis of His228 to tyrosine and glycine in this study results in a complete or significant loss of activity.