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1.
The fumarylacetoacetate hydrolase (FAH) superfamily of enzymes: multifunctional enzymes from microbes to mitochondria.
Weiss, AKH, Loeffler, JR, Liedl, KR, Gstach, H, Jansen-Dürr, P
Biochemical Society transactions. 2018;(2):295-309
Abstract
Prokaryotic and eukaryotic fumarylacetoacetate hydrolase (FAH) superfamily members, sharing conserved regions that form the so-called FAH-domain, catalyze a remarkable variety of reactions. These enzymes are essential in the metabolic pathways to degrade aromatic compounds in prokaryotes and eukaryotes. It appears that prokaryotic FAH superfamily members evolved mainly to allow microbes to generate energy and useful metabolites from complex carbon sources. We review recent findings, indicating that both prokaryotic and eukaryotic members of the FAH superfamily also display oxaloacetate decarboxylase (ODx) activity. The identification of human FAH domain-containing protein 1 as mitochondrial ODx regulating mitochondrial function supports the new concept that, during evolution, eukaryotic FAH superfamily members have acquired important regulatory functions beyond catabolism of complex carbon sources. Molecular studies on the evolution and function of FAH superfamily members are expected to provide new mechanistic insights in their physiological roles.
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2.
Febrile temperature reprograms by redox-mediated signaling the mitochondrial metabolic phenotype in monocyte-derived dendritic cells.
Menga, M, Trotta, R, Scrima, R, Pacelli, C, Silvestri, V, Piccoli, C, Capitanio, N, Liso, A
Biochimica et biophysica acta. Molecular basis of disease. 2018;(3):685-699
Abstract
Fever-like hyperthermia is known to stimulate innate and adaptive immune responses. Hyperthermia-induced immune stimulation is also accompanied with, and likely conditioned by, changes in the cell metabolism and, in particular, mitochondrial metabolism is now recognized to play a pivotal role in this context, both as energy supplier and as signaling platform. In this study we asked if challenging human monocyte-derived dendritic cells with a relatively short-time thermal shock in the fever-range, typically observed in humans, caused alterations in the mitochondrial oxidative metabolism. We found that following hyperthermic stress (3h exposure at 39°C) TNF-α-releasing dendritic cells undergo rewiring of the oxidative metabolism hallmarked by decrease of the mitochondrial respiratory activity and of the oxidative phosphorylation and increase of lactate production. Moreover, enhanced production of reactive oxygen and nitrogen species and accumulation of mitochondrial Ca2+ was consistently observed in hyperthermia-conditioned dendritic cells and exhibited a reciprocal interplay. The hyperthermia-induced impairment of the mitochondrial respiratory activity was (i) irreversible following re-conditioning of cells to normothermia, (ii) mimicked by exposing normothermic cells to the conditioned medium of the hyperthermia-challenged cells, (iii) largely prevented by antioxidant and inhibitors of the nitric oxide synthase and of the mitochondrial calcium porter, which also inhibited release of TNF-α. These observations combined with gene expression analysis support a model based on a thermally induced autocrine signaling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells.
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3.
Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes.
Valvassori, SS, Bavaresco, DV, Feier, G, Cechinel-Recco, K, Steckert, AV, Varela, RB, Borges, C, Carvalho-Silva, M, Gomes, LM, Streck, EL, et al
Psychiatry research. 2018;:192-201
Abstract
The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.
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4.
Signaling pathways governing iron homeostasis in budding yeast.
Martins, TS, Costa, V, Pereira, C
Molecular microbiology. 2018;(4):422-432
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Abstract
Iron is an essential element for eukaryotes as it participates as a redox-active co-factor in many biological processes. Since iron is also potentially toxic, iron levels are carefully regulated. In the yeast Saccharomyces cerevisiae, iron homeostasis is maintained by the transcriptional control of the iron acquisition systems (iron regulon), mainly by the iron-responsive transcriptional factors Aft1p and Yap5p. Intracellular iron is stored in the vacuole, mobilized for other locations when necessary, particularly for the mitochondria, the major site of iron-utilizing pathways. Mitochondria also play an additional role as a sensor for the regulation of cellular iron acquisition and intracellular distribution. Mounting evidence suggest that iron acquisition systems are not only responsive to iron levels but also to signaling pathways. The most recognized is the activation of the iron regulon at the diauxic shift, oppositely regulated by PKA and SNF1 kinases, major regulators of glucose signaling. Hog1p, a MAP kinase involved in stress responses, also negatively regulates iron uptake by phosphorylating Aft1p. In this review, we address organellar signaling and signal transduction pathways that play a major role in the coordination of iron homeostasis with cell growth and division.
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The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights.
Cecchino, GN, Seli, E, Alves da Motta, EL, García-Velasco, JA
Reproductive biomedicine online. 2018;(6):686-697
Abstract
Mitochondria have been implicated as key factors regulating female reproductive processes. Notable progress has been made in determining the role of mitochondria with respect to oocyte maturation, fertilization and early embryo development. In addition, mitochondrial function and dysfunction has been the subject of various studies in ovarian ageing and metabolic stress models. However, the overall mitochondrial impact on female fertility is yet to be uncovered. The mitochondrial DNA content of granulosa, cumulus and trophectoderm cells is being explored as a biomarker of oocyte quality and embryo viability. As growing evidence suggests that embryo potential could be related to the ability of oocyte mitochondria to generate energy, efforts have been made to investigate the possibility of improving mitochondrial capacity in women with poor outcomes after treatment with assistedreproductive technologies. Thus far, therapeutic attempts have focused mainly on using nutrients to restore mitochondrial function and transferring mitochondria from autologous germline precursor cells. Moreover, new perspectives on optimizing infertility treatments have arisen with modern mitochondrial replacement therapies, which are being applied in women with mitochondrial disease-causing mutations. This review explores aspects of the distinctive contribution of mitochondria to reproductive processes and discusses current and emerging clinical implications.
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Mitochondria-associated membranes (MAMs) and pathologies.
Pinton, P
Cell death & disease. 2018;(4):413
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Pluripotent Stem Cells for Uncovering the Role of Mitochondria in Human Brain Function and Dysfunction.
Zink, A, Priller, J, Prigione, A
Journal of molecular biology. 2018;(7):891-903
Abstract
Mitochondrial dysfunctions are a known pathogenetic mechanism of a number of neurological and psychiatric disorders. At the same time, mutations in genes encoding for components of the mitochondrial respiratory chain cause mitochondrial diseases, which commonly exhibit neurological symptoms. Mitochondria are therefore critical for the functionality of the human nervous system. The importance of mitochondria stems from their key roles in cellular metabolism, calcium handling, redox and protein homeostasis, and overall cellular homeostasis through their dynamic network. Here, we describe how the use of pluripotent stem cells (PSCs) may help in addressing the physiological and pathological relevance of mitochondria for the human nervous system. PSCs allow the generation of patient-derived neurons and glia and the identification of gene-specific and mutation-specific cellular phenotypes via genome engineering approaches. We discuss the recent advances in PSC-based modeling of brain diseases and the current challenges of the field. We anticipate that the careful use of PSCs will improve our understanding of the impact of mitochondria in neurological and psychiatric disorders and the search for effective therapeutic avenues.
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8.
Human cellular mitochondrial remodelling is governed by miR-2909 RNomics.
Malik, D, Kaul, D
PloS one. 2018;(9):e0203614
Abstract
BACKGROUND There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival. MATERIAL AND METHODS Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1α), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARγ) nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post-transfection using RT-qPCR and cellular ultrastructural features induced by miR-2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph. RESULTS Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced by ectopic miR-2909 expression in human PBMCs. CONCLUSION Based upon these results we propose that AATF gene-encoded miR-2909 may act as an epigenetic switch for cellular aerobic-glycolysis to ensure de-differentiation.
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9.
MiR-195 modulates oxidative stress-induced apoptosis and mitochondrial energy production in human trophoblasts via flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 and pyruvate dehydrogenase phosphatase regulatory subunit.
Wang, H, Zhang, L, Guo, X, Bai, Y, Li, YX, Sha, J, Peng, C, Wang, YL, Liu, M
Journal of hypertension. 2018;(2):306-318
Abstract
OBJECTIVE Preeclampsia is a severe pregnancy-specific syndrome defined as newly onset hypertension and proteinuria. Abnormal placental development has been generally accepted as the initial cause of the disorder. Recently, miR-195 was identified as one of the downregulated small RNAs in preeclamptic placentas. METHODS The potential targets of miR-195 in human trophoblast cells were screened by isobaric tags for relative and absolute quantification-based mass spectrum analysis. Localization of miR-195 and its targets was examined by in-situ hybridization and immunohistochemistry in human placenta. Real-time PCR, western blotting and luciferase assay were used for target validation. Apoptosis was accessed by Annexin V/PI costaining, whereas mitochondrial function by ATP measurement and tetramethylrhodamine ethyl ester fluorescence. RESULTS Two mitochondria-associated proteins, flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 (FOXRED1) and pyruvate dehydrogenase phosphatase regulatory subunit (PDPR), were identified as targets of miR-195. Overexpression of miR-195 in HTR8/SVneo cells resulted in enhanced apoptosis, decreased mitochondrial membrane potential and cellular ATP content upon hydrogen peroxide stimulation. The effects could be partially rescued by FOXRED1 or PDPR. In preeclamptic patients, lowered circulating level of miR-195 were found at early-to-mid gestation and term pregnancy, and marked increase in FOXRED1 and PDPR expression were observed in the placenta when compared with gestational week-matched controls. In addition, chronic hydrogen peroxide stimuli suppressed miR-195 expression in trophoblast cells. CONCLUSION MiR-195 could suppress mitochondrial energy production via targeting FOXRED1 and PDPR, and lead to trophoblast cell apoptosis under oxidative stress. In preeclamptic placenta, lowered level of miR-195 might be induced by chorionic oxidative stress and subsequently form a compensation mechanism to defend the disturbed energy production and cell apoptosis upon oxidative stress.
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10.
Acute loss of iron-sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells.
Crooks, DR, Maio, N, Lane, AN, Jarnik, M, Higashi, RM, Haller, RG, Yang, Y, Fan, TW, Linehan, WM, Rouault, TA
The Journal of biological chemistry. 2018;(21):8297-8311
Abstract
Iron-sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant-negative variants of the primary Fe-S biogenesis scaffold protein iron-sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming associated with loss of Fe-S-containing proteins in several major cellular compartments. Using multiple metabolomics platforms, we observed a ∼12-fold increase in intracellular citrate content in Fe-S-deficient cells, a surge that was due to loss of aconitase activity. The excess citrate was generated from glucose-derived acetyl-CoA, and global analysis of cellular lipids revealed that fatty acid biosynthesis increased markedly relative to cellular proliferation rates in Fe-S-deficient cells. We also observed intracellular lipid droplet accumulation in both acutely Fe-S-deficient cells and iron-starved cells. We conclude that deficient Fe-S biogenesis and acute iron deficiency rapidly increase cellular citrate concentrations, leading to fatty acid synthesis and cytosolic lipid droplet formation. Our findings uncover a potential cause of cellular steatosis in nonadipose tissues.