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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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4.
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.
A Peptoid Delivers CoQ-derivative to Plant Mitochondria via Endocytosis.
Asfaw, KG, Liu, Q, Maisch, J, Münch, SW, Wehl, I, Bräse, S, Bogeski, I, Schepers, U, Nick, P
Scientific reports. 2019;(1):9839
Abstract
Controlled delivery of molecules interfering specifically with target activities in a cell of interest can be a powerful tool for experimental manipulation, because it can be administered at a defined time point and does not require genetic transformation, which in some systems is difficult and time consuming. Peptides as versatile tools that can be tailored for binding numerous binding partners, are of special interest. However, their passage through membranes, their intracellular targeting, and their sensitivity to proteases is limiting. The use of peptoids, where cationic amino-acid side chains are linked to nitrogen (rather than to carbon) of the peptide bond, can circumvent these limitations, because they are not cleavable by proteases. In the current work, we provide a proof-of-concept that such Trojan Peptoids, the plant PeptoQ, can be used to target a functional cargo (i.e. a rhodamine-labelled peptoid and a coenzyme Q10 derivative) into mitochondria of tobacco BY-2 cells as experimental model. We show that the uptake is specific for mitochondria, rapid, dose-dependent, and requires clathrin-mediated endocytosis, as well as actin filaments, while microtubules seem to be dispensable. Viability of the treated cells is not affected, and they show better survival under salt stress, a condition that perturbs oxidative homeostasis in mitochondria. In congruence with improved homeostasis, we observe that the salt induced accumulation of superoxide is mitigated and even inverted by pretreatment with PeptoQ. Using double labelling with appropriate fluorescent markers, we show that targeting of this Trojan Peptoid to the mitochondria is not based on a passage through the plasma membrane (as thought hitherto), but on import via endocytotic vesicles and subsequent accumulation in the mitochondrial intermembrane space, from where it can enter the matrix, e.g. when the permeability of the inner membrane is increased under salt stress.
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7.
Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation.
Pirisinu, M, Blasco, P, Tian, X, Sen, Y, Bode, AM, Liu, K, Dong, Z
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019;(7):7970-7984
Abstract
Pharmaceutical interest in targeting mitochondria is increasing because of their contribution in incurable diseases. However, the inner mitochondrial layer represents a major hurdle to overcome for most drugs. Penetrating peptides are a promising strategy for drug delivery, but the absence of standard principles and reliable prediction tools limits the design and discovery of sequences with improved organelle specificity. In our hypothesis, peptide local flexibility represents a valuable source to predict peptide performance. Here, a pool of short nonnatural peptides was designed with the same amino acid content but different positioning. Molecular dynamics and membrane-transfer simulations were used to generate the low-energy conformers in extra, intracellular, and membrane-inserted environments. The contributions of the hydrophobic and hydrophilic side chain-exposed surfaces revealed that the amino acid's relative position significantly affected the simulated peptide's dynamics. Based on the structural versatility, we predicted the peptides' behavior and the sequence with the most efficient membrane penetration and mitochondrial localization. The prediction and the improved performance of our peptides were experimentally confirmed and compared with a reported mitochondrial-targeting sequence. We demonstrated that an accurate understanding of the structural versatility is a valid aid for future works in designing sequences with improved mitochondrial targeting.-Pirisinu, M., Blasco, P., Tian, X., Sen, Y., Bode, A. M., Liu, K., Dong, Z. Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation.
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8.
Structural basis for the interaction of the chaperone Cbp3 with newly synthesized cytochrome b during mitochondrial respiratory chain assembly.
Ndi, M, Masuyer, G, Dawitz, H, Carlström, A, Michel, M, Elofsson, A, Rapp, M, Stenmark, P, Ott, M
The Journal of biological chemistry. 2019;(45):16663-16671
Abstract
Assembly of the mitochondrial respiratory chain requires the coordinated synthesis of mitochondrial and nuclear encoded subunits, redox co-factor acquisition, and correct joining of the subunits to form functional complexes. The conserved Cbp3-Cbp6 chaperone complex binds newly synthesized cytochrome b and supports the ordered acquisition of the heme co-factors. Moreover, it functions as a translational activator by interacting with the mitoribosome. Cbp3 consists of two distinct domains: an N-terminal domain present in mitochondrial Cbp3 homologs and a highly conserved C-terminal domain comprising a ubiquinol-cytochrome c chaperone region. Here, we solved the crystal structure of this C-terminal domain from a bacterial homolog at 1.4 Å resolution, revealing a unique all-helical fold. This structure allowed mapping of the interaction sites of yeast Cbp3 with Cbp6 and cytochrome b via site-specific photo-cross-linking. We propose that mitochondrial Cbp3 homologs carry an N-terminal extension that positions the conserved C-terminal domain at the ribosomal tunnel exit for an efficient interaction with its substrate, the newly synthesized cytochrome b protein.
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9.
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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10.
A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis.
Besse, L, Besse, A, Mendez-Lopez, M, Vasickova, K, Sedlackova, M, Vanhara, P, Kraus, M, Bader, J, Ferreira, RB, Castellano, RK, et al
Haematologica. 2019;(9):e415-e419