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1.
Mitochondrial dysfunction in metabolic syndrome.
Prasun, P
Biochimica et biophysica acta. Molecular basis of disease. 2020;(10):165838
Abstract
Metabolic syndrome is co-occurrence of obesity, insulin resistance, atherogenic dyslipidemia (high triglyceride, low high density lipoprotein cholesterol), and hypertension. It is a global health problem. An estimated 20%-30% of adults of the world have metabolic syndrome. Metabolic syndrome is associated with increased risk of type 2 diabetes mellitus, nonalcoholic fatty liver disease, myocardial infarction, and stroke. Thus, it is a major cause of morbidity and mortality worldwide. However, molecular pathogenesis of metabolic syndrome is not well known. Recently, there has been interest in the role of mitochondria in pathogenesis of metabolic problems such as obesity, metabolic syndrome, and type 2 diabetes mellitus. Mitochondrial dysfunction contributes to the oxidative stress and systemic inflammation seen in metabolic syndrome. Role of mitochondria in the pathogenesis of metabolic syndrome is intriguing but far from completely understood. However, a better understanding will be very rewarding as it may lead to novel approaches to control this major public health problem. This brief review explores pathogenesis of metabolic syndrome from a mitochondrial perspective.
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2.
Functional properties and mode of regulation of the mitochondrial Na+/Ca2+ exchanger, NCLX.
Kostic, M, Sekler, I
Seminars in cell & developmental biology. 2019;:59-65
Abstract
Mitochondrial Ca2+ transient is the earliest discovered organellar Ca2+ signaling pathway. It consist of a Ca2+ influx, mediated by mitochondrial Ca2+ uniporter (MCU), and mitochondrial Ca2+ efflux mediated by a Na+/Ca2+ exchanger (NCLX). Mitochondrial Ca2+ signaling machinery plays a fundamental role in linking metabolic activity to cellular Ca2+ signaling, and in controlling local Ca2+ concertation in distinct cellular compartments. Impaired balance between mitochondrial Ca2+ influx and efflux leads to mitochondrial Ca2+ overload, an early and key event in ischemic or neurodegenerative syndromes. Molecular identification of NCLX and MCU happened only recently. Surprisingly, MCU knockout yielded a relatively mild phenotype while conditional knockout of NCLX led to a rapid fatal heart failure. Here we will focus on recent functional and molecular studies on NCLX structure and its mode of regulation. We will describe the unique crosstalk of this exchanger with Na+ and Ca2+ signaling pathways in the cell membrane and the endoplasmic reticulum, and with protein kinases that posttranslationally modulate NCLX activity. We will critically compare selectivity of pharmacological blockers versus molecular control of NCLX expression and activity. Finally we will discuss why this exchanger is essential for survival and can serve as an attractive therapeutic target.
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3.
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis.
Archid, R, Solass, W, Tempfer, C, Königsrainer, A, Adolph, M, Reymond, MA, Wilson, RB
International journal of molecular sciences. 2019;(21)
Abstract
: Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.
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4.
Mitochondrial Quality Control as a Therapeutic Target.
Suliman, HB, Piantadosi, CA
Pharmacological reviews. 2016;(1):20-48
Abstract
In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.
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5.
An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.
Sheldon, CA, Kwon, YJ, Liu, GT, McCormack, SE
Pediatric research. 2015;(2):282-9
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Abstract
Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.
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6.
Metabolic features of the cell danger response.
Naviaux, RK
Mitochondrion. 2014;:7-17
Abstract
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
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7.
NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.
Izzo, A, Manco, R, Bonfiglio, F, Calì, G, De Cristofaro, T, Patergnani, S, Cicatiello, R, Scrima, R, Zannini, M, Pinton, P, et al
Human molecular genetics. 2014;(16):4406-19
Abstract
Mitochondrial dysfunction, which is consistently observed in Down syndrome (DS) cells and tissues, might contribute to the severity of the DS phenotype. Our recent studies on DS fetal hearts and fibroblasts have suggested that one of the possible causes of mitochondrial dysfunction is the downregulation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α or PPARGC1A)--a key modulator of mitochondrial function--and of several nuclear-encoded mitochondrial genes (NEMGs). Re-analysis of publicly available expression data related to manipulation of chromosome 21 (Hsa21) genes suggested the nuclear receptor interacting protein 1 (NRIP1 or RIP140) as a good candidate Hsa21 gene for NEMG downregulation. Indeed, NRIP1 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PGC-1α. To establish whether NRIP1 overexpression in DS downregulates both PGC-1α and NEMGs, thereby causing mitochondrial dysfunction, we used siRNAs to decrease NRIP1 expression in trisomic human fetal fibroblasts. Levels of PGC-1α and NEMGs were increased and mitochondrial function was restored, as shown by reactive oxygen species decrease, adenosine 5'-triphosphate (ATP) production and mitochondrial activity increase. These findings indicate that the Hsa21 gene NRIP1 contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the NRIP1-PGC-1α axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS.
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8.
Human choline dehydrogenase: medical promises and biochemical challenges.
Salvi, F, Gadda, G
Archives of biochemistry and biophysics. 2013;(2):243-52
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Abstract
Human choline dehydrogenase (CHD) is located in the inner membrane of mitochondria primarily in liver and kidney and catalyzes the oxidation of choline to glycine betaine. Its physiological role is to regulate the concentrations of choline and glycine betaine in the blood and cells. Choline is important for regulation of gene expression, the biosynthesis of lipoproteins and membrane phospholipids and for the biosynthesis of the neurotransmitter acetylcholine; glycine betaine plays important roles as a primary intracellular osmoprotectant and as methyl donor for the biosynthesis of methionine from homocysteine, a required step for the synthesis of the ubiquitous methyl donor S-adenosyl methionine. Recently, CHD has generated considerable medical attention due to its association with various human pathologies, including male infertility, homocysteinuria, breast cancer and metabolic syndrome. Despite the renewed interest, the biochemical characterization of the enzyme has lagged behind due to difficulties in the obtainment of purified, active and stable enzyme. This review article summarizes the medical relevance and the physiological roles of human CHD, highlights the biochemical knowledge on the enzyme, and provides an analysis based on the comparison of the protein sequence with that of bacterial choline oxidase, for which structural and biochemical information is available.
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9.
[Case of fanconi syndrome positive for anti-M2 antibodies revealed by severe hypokalemia and multiple bone fracture].
Hara, M, Miyazawa, R, Takagi, A, Kado, H, Maki, K, Sawada, K, You, K, Hatta, T
Nihon Jinzo Gakkai shi. 2011;(5):719-25
Abstract
A 38-year-old female developed pain in the right leg in 2006. In 2007, the diagnosis of femoral head necrosis was made based on MR images, and femoral head prosthetic replacement was performed. In April 2009, she visited a local hospital for low back pain, and was referred to our department due to electrolyte abnormalities on hemanalysis. Since marked hypokalemia (K=2.5 mEq/L), hypophosphatemia, hyperchloric metabolic acidosis, proteinuria, and urinary blood sugar suggested Fanconi syndrome, she was admitted for close examination. Bone survey showed a marked decrease in the amount of bone particularly in the four limbs and fracture at the proximal 1/3 of the left ulnar bone. In the lumbar spine, scoliosis and vertebral deformity were observed. Since impaired P re-absorption and unselected aminoaciduria and osteomalacia were also present, the diagnosis of Fanconi syndrome was made. On admission, ventricular tachycardia developed due to hypokalemia, requiring immediate electrolyte correction. For differentiation from acquired Fanconi syndrome, various examinations were performed. No apparent cause was found except for the positive antimitochondrial antibody-M2 (anti-M2). In this case, no data suggested liver dysfunction, and subsequent liver biopsy also showed no significant pathological findings pointing to PBC. We encountered a patient with Fanconi syndrome positive for anti-M2. This case may attract interest, particularly in the mechanism of nephropathy due to anti-M2, and therefore, this case is reported with a literature review.
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10.
Dynamic simulations on the mitochondrial fatty acid beta-oxidation network.
Modre-Osprian, R, Osprian, I, Tilg, B, Schreier, G, Weinberger, KM, Graber, A
BMC systems biology. 2009;:2
Abstract
BACKGROUND The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress). RESULTS A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described. CONCLUSION In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.