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1.
Influence of mitochondrial and systemic iron levels in heart failure pathology.
Lupu, M, Tudor, DV, Filip, GA
Heart failure reviews. 2019;(5):647-659
Abstract
Iron deficiency or overload poses an increasingly complex issue in cardiovascular disease, especially heart failure. The potential benefits and side effects of iron supplementation are still a matter of concern, even though current guidelines suggest therapeutic management of iron deficiency. In this review, we sought to examine the iron metabolism and to identify the rationale behind iron supplementation and iron chelation. Cardiovascular disease is increasingly linked with iron dysmetabolism, with an increased proportion of heart failure patients being affected by decreased plasma iron levels and in turn, by the decreased quality of life. Multiple studies have concluded on a benefit of iron administration, even if just for symptomatic relief. However, new studies field evidence for negative effects of dysregulated non-bound iron and its reactive oxygen species production, with concern to heart diseases. The molecular targets of iron usage, such as the mitochondria, are prone to deleterious effects of the polyvalent metal, added by the scarcely described processes of iron elimination. Iron supplementation and iron chelation show promise of therapeutic benefit in heart failure, with the extent and mechanisms of both prospects not being entirely understood. It may be that a state of decreased systemic and increased mitochondrial iron levels proves to be a useful frame for future advancements in understanding the interconnection of heart failure and iron metabolism.
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2.
Cardiomyocyte mitochondrial dysfunction in diabetes and its contribution in cardiac arrhythmogenesis.
El Hadi, H, Vettor, R, Rossato, M
Mitochondrion. 2019;:6-14
Abstract
Cardiovascular disease is the leading cause of diabetes-related morbidity and mortality. It is widely accepted that heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Mitochondria are the center of fatty acid (FA) and glucose metabolism and thus are likely to be impacted by impaired metabolism associated with diabetes. Although the cause of this increased heart failure risk is multifactorial, increasing evidence points toward a crucial role for cardiomyocyte mitochondria dysfunction. Altered energy metabolism, defects in mitochondrial dynamics, increased oxidative stress, impaired calcium (Ca2+) handling and mitochondria-induced cell death are observed in mitochondria of diabetic myocardium. In addition, mitochondrial dysfunction appears to contribute substantially to the origin of arrhythmias in diabetic hearts. The current review will describe these mitochondrial abnormalities in cardiomyocytes attempting to provide an overview of underlying mechanisms. Finally, we briefly discuss the potential link between mitochondrial malfunction and arrhythmogenesis.
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3.
Connecting iron regulation and mitochondrial function in Cryptococcus neoformans.
Horianopoulos, LC, Kronstad, JW
Current opinion in microbiology. 2019;:7-13
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Abstract
Iron acquisition is essential for the proliferation of microorganisms, and human pathogens such as the fungus Cryptococcus neoformans must use sophisticated uptake mechanisms to overcome host iron sequestration. Iron is of particular interest for C. neoformans because its availability is an important cue for the elaboration of virulence factors. In fungi, extracellular iron is taken up through high affinity, low affinity, siderophore-mediated, and heme uptake pathways, and the details of these mechanisms are under active investigation in C. neoformans. Following uptake, iron is transported to intracellular organelles including mitochondria where it is used in heme biosynthesis and the synthesis of iron-sulfur (Fe-S) cluster precursors. One Fe-S cluster binding protein of note is the monothiol glutaredoxin Grx4 which has emerged as a master regulator of iron sensing in C. neoformans and other fungi through its influence on the expression of proteins for iron uptake or use. The activity of Grx4 likely occurs through interactions with Fe-S clusters and transcription factors known to control expression of the iron-related functions. Although the extent to which Grx4 controls the iron regulatory network is still being investigated in C. neoformans, it is remarkable that it also influences the expression of many genes encoding mitochondrial functions. Coupled with recent studies linking mitochondrial morphology and electron transport to virulence factor elaboration, there is an emerging appreciation of mitochondria as central players in cryptococcal disease.
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Mitochondrial Flexibility of Breast Cancers: A Growth Advantage and a Therapeutic Opportunity.
Avagliano, A, Ruocco, MR, Aliotta, F, Belviso, I, Accurso, A, Masone, S, Montagnani, S, Arcucci, A
Cells. 2019;(5)
Abstract
Breast cancers are very heterogeneous tissues with several cell types and metabolic pathways together sustaining the initiation and progression of disease and contributing to evasion from cancer therapies. Furthermore, breast cancer cells have an impressive metabolic plasticity that is regulated by the heterogeneous tumour microenvironment through bidirectional interactions. The structure and accessibility of nutrients within this unstable microenvironment influence the metabolism of cancer cells that shift between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to produce adenosine triphosphate (ATP). In this scenario, the mitochondrial energetic pathways of cancer cells can be reprogrammed to modulate breast cancer's progression and aggressiveness. Moreover, mitochondrial alterations can lead to crosstalk between the mitochondria and the nucleus, and subsequently affect cancer tissue properties. This article reviewed the metabolic plasticity of breast cancer cells, focussing mainly on breast cancer mitochondrial metabolic reprogramming and the mitochondrial alterations influencing nuclear pathways. Finally, the therapeutic strategies targeting molecules and pathways regulating cancer mitochondrial alterations are highlighted.
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5.
Steroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation.
Tugaeva, KV, Sluchanko, NN
Biochemistry. Biokhimiia. 2019;(Suppl 1):S233-S253
Abstract
Steroidogenesis takes place mainly in adrenal and gonadal cells that produce a variety of structurally similar hormones regulating numerous body functions. The rate-limiting stage of steroidogenesis is cholesterol delivery to the inner mitochondrial membrane, where it is converted by cytochrome P450scc into pregnenolone, a common precursor of all steroid hormones. The major role of supplying mitochondria with cholesterol belongs to steroidogenic acute regulatory protein (STARD1). STARD1, which is synthesized de novo as a precursor containing mitochondrial localization sequence and sterol-binding domain, significantly accelerates cholesterol transport and production of pregnenolone. Despite a tremendous interest in STARD1 fueled by its involvement in hereditary diseases and extensive efforts of numerous laboratories worldwide, many aspects of STARD1 structure, functioning, and regulation remain obscure and debatable. This review presents current concepts on the structure of STARD1 and other lipid transfer proteins, the role of STARD1 in steroidogenesis, and the mechanism of its functioning, as well as identifies the most controversial and least studied questions related to the activity of this protein.
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6.
Mitophagy and mitochondrial integrity in cardiac ischemia-reperfusion injury.
Yang, M, Linn, BS, Zhang, Y, Ren, J
Biochimica et biophysica acta. Molecular basis of disease. 2019;(9):2293-2302
Abstract
Ischemia-reperfusion injury (IR injury), produced by initial interruption and subsequent restoration of organ blood flow, is an important clinical dilemma accompanied by various cardiac reperfusion strategies following acute myocardial infarction (AMI). Although the restored blood flow is necessary for oxygen and nutrient supply, reperfusion often results in pathological sequelae leading to elevated ischemic damage. Among various theories postulated for IR injury including vascular leakage, oxidative stress, leukocyte entrapment, inflammation and apoptosis, mitochondrial dysfunction plays an essential role in mediating pathophysiological processes with recent evidence depicting a pivotal role for impaired mitophagy in mitochondrial injury. Given the critical role for mitophagy in mitochondrial quality control and the recent reports supporting a tie between mitophagy and IR injury, this review will revisit the contemporary understanding of mitophagy in the regulation of cardiac homeostasis and update recent progresses with regards to mitophagy and cardiac IR injury. We hope to establish a role for mitophagy as a potential therapeutic target in the management of IR injury.
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7.
Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm.
Huertas, JR, Casuso, RA, Agustín, PH, Cogliati, S
Oxidative medicine and cellular longevity. 2019;:7058350
Abstract
Skeletal muscles require the proper production and distribution of energy to sustain their work. To ensure this requirement is met, mitochondria form large networks within skeletal muscle cells, and during exercise, they can enhance their functions. In the present review, we discuss recent findings on exercise-induced mitochondrial adaptations. We emphasize the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation as mechanisms triggered by exercise that may increase the function of skeletal muscles. Finally, we highlight the possible effects of nutraceutical compounds on mitochondrial performance during exercise and outline the use of exercise as a therapeutic tool in noncommunicable disease prevention. The resulting picture shows that the modulation of mitochondrial activity by exercise is not only fundamental for physical performance but also a key point for whole-organism well-being.
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Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease.
Ducasa, GM, Mitrofanova, A, Fornoni, A
Current diabetes reports. 2019;(12):144
Abstract
PURPOSE OF REVIEW The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. RECENT FINDINGS Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.
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Hypertension linked to allostatic load: from psychosocial stress to inflammation and mitochondrial dysfunction.
Mocayar Marón, FJ, Ferder, L, Saraví, FD, Manucha, W
Stress (Amsterdam, Netherlands). 2019;(2):169-181
Abstract
Although a large number of available treatments and strategies, the prevalence of cardiovascular diseases continues to grow worldwide. Emerging evidence supports the notion of counteracting stress as a critical component of a comprehensive therapeutic strategy for cardiovascular disease. Indeed, an unhealthy lifestyle is a burden to biological variables such as plasma glucose, lipid profile, and blood pressure control. Recent findings identify allostatic load as a new paradigm for an integrated understanding of the importance of psychosocial stress and its impact on the development and maintenance of cardiovascular disease. Allostasis complement homeostasis and integrates behavioral and physiological mechanisms by which genes, early experiences, environment, lifestyle, diet, sleep, and physical exercise can modulate and adapt biological responses at the cellular level. For example, variability is a physiological characteristic of blood pressure necessary for survival and the allostatic load in hypertension can contribute to its related cardiovascular morbidity and mortality. Therefore, the current review will focus on the mechanisms that link hypertension to allostatic load, which includes psychosocial stress, inflammation, and mitochondrial dysfunction. We will describe and discuss new insights on neuroendocrine-immune effects linked to allostatic load and its impact on the cellular and molecular responses; the links between allostatic load, inflammation, and endothelial dysfunction; the epidemiological evidence supporting the pathophysiological origins of hypertension; and the biological embedding of allostatic load and hypertension with an emphasis on mitochondrial dysfunction.
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10.
Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation.
Wang, ZB, Liu, JY, Xu, XJ, Mao, XY, Zhang, W, Zhou, HH, Liu, ZQ
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019;:109068
Abstract
NBIA (Neurodegeneration with brain iron accumulation) is a group of inherited neurologic disorders characterized by marked genetic heterogeneity, in which iron atypical accumulates in basal ganglia resulting in brain magnetic resonance imaging changes, histopathological abnormalities, and neuropsychiatric clinical symptoms. With the rapid development of high-throughput sequencing technologies, ten candidate genes have been identified, including PANK2, PLA2G6, C19orf12, WDR45, FA2H, ATP13A2, FTL, CP, C2orf37, and COASY. They are involved in seemingly unrelated cellular pathways, such as iron homeostasis (FTL, CP), lipid metabolism (PLA2G6, C19orf12, FA2H), Coenzyme A synthesis (PANK2, COASY), and autophagy (WDR45, ATP13A2). In particular, PANK2, COASY, PLA2G6, and C19orf12 are located on mitochondria, which associate with certain subtypes of NBIA showing mitochondria dysregulation. However, the relationships among those four genes are still unclear. Therefore, this review is specifically focused on dysregulation of mitochondria in NBIA and afore-mentioned four genes, with summaries of both pathological and clinical findings.