scholarly journals Mitochondrial Calcium Regulation of Redox Signaling in Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 432 ◽  
Author(s):  
Céline Delierneux ◽  
Sana Kouba ◽  
Santhanam Shanmughapriya ◽  
Marie Potier-Cartereau ◽  
Mohamed Trebak ◽  
...  
Keyword(s):  
Metabolic Flux ◽  
Cellular Proliferation ◽  
Atp Synthesis ◽  
Redox Signaling ◽  
Mitochondrial Enzymes ◽  
Cellular Processes ◽  
Transport Chain ◽  
Atp Generation ◽  
And Function ◽  
Ca2 Channels

Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.

scholarly journals Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 261 ◽  
Author(s):  
Jickky Palmae Sarathy ◽  
Gerhard Gruber ◽  
Thomas Dick
Keyword(s):  
Electron Transport ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Mechanisms Of Action ◽  
Direct Mechanism ◽  
Transport Chain ◽  
Ring Rotation ◽  
New Findings ◽  
Atp Generation ◽  
Resistance Mutants

Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme’s catalytic α3β3-headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme’s ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α3β3-headpiece. However, this mechanism is controversial as the drug’s binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ’s mechanisms of action. In this review, we first summarize discoveries on BDQ’s mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ’s anti-mycobacterial activity.

scholarly journals Structure and function of an unusual flavodoxin from the domainArchaea

2019 ◽  
Vol 116 (51) ◽  
pp. 25917-25922 ◽  
Author(s):  
Divya Prakash ◽  
Prashanti R. Iyer ◽  
Suharti Suharti ◽  
Karim A. Walters ◽  
Michel Geovanni Santiago-Martinez ◽  
...  
Keyword(s):  
Atp Synthesis ◽  
Flavin Mononucleotide ◽  
Methanosarcina Acetivorans ◽  
Physiological Characterization ◽  
Electron Transfer Proteins ◽  
Reduction Potentials ◽  
Transport Chain ◽  
Membrane Bound ◽  
And Function

Flavodoxins, electron transfer proteins essential for diverse metabolisms in microbes from the domainBacteria, are extensively characterized. Remarkably, although genomic annotations of flavodoxins are widespread in microbes from the domainArchaea, none have been isolated and characterized. Herein is described the structural, biochemical, and physiological characterization of an unusual flavodoxin (FldA) fromMethanosarcina acetivorans, an acetate-utilizing methane-producing microbe of the domainArchaea. In contrast to all flavodoxins, FldA is homodimeric, markedly less acidic, and stabilizes an anionic semiquinone. The crystal structure reveals an flavin mononucleotide (FMN) binding site unique from all other flavodoxins that provides a rationale for stabilization of the anionic semiquinone and a remarkably low reduction potentials for both the oxidized/semiquinone (−301 mV) and semiquinone/hydroquinone couples (−464 mV). FldA is up-regulated in acetate-grown versus methanol-grown cells and shown here to substitute for ferredoxin in mediating the transfer of low potential electrons from the carbonyl of acetate to the membrane-bound electron transport chain that generates ion gradients driving ATP synthesis. FldA offers potential advantages over ferredoxin by (i) sparing iron for abundant iron-sulfur proteins essential for acetotrophic growth and (ii) resilience to oxidative damage.

scholarly journals The mitochondrial calcium uniporter compensates for Complex I dysfunction

2021 ◽  
Author(s):  
Enrique Balderas ◽  
David Eberhardt ◽  
John Pleinis ◽  
Salah Sommakia ◽  
Anthony Balynas ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Complex I ◽  
Atp Synthesis ◽  
Signaling Mechanism ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Complex I Deficiency ◽  
Transport Chain ◽  
Energy Synthesis ◽  
And Function

Abstract Calcium (Ca2+) entering mitochondria potently stimulates ATP synthesis. Increases in Ca2+ preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial Ca2+ uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain (ETC). In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover (CLIPT). When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in Ca2+ influx during Complex I impairment.

Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle

2011 ◽  
Vol 43 (6) ◽  
pp. 271-285 ◽  
Author(s):  
Darryl L. Hadsell ◽  
Walter Olea ◽  
Jerry Wei ◽  
Marta L. Fiorotto ◽  
Risë K. Matsunami ◽  
...  
Keyword(s):  
Electron Transport ◽  
Mitochondrial Biogenesis ◽  
Electron Transport Chain ◽  
Atp Synthesis ◽  
Mammary Tissue ◽  
Early Lactation ◽  
Amp Kinase ◽  
Transport Chain ◽  
Mammary Cell ◽  
And Function

The regulation of mitochondrial biogenesis and function in the lactating mammary cell is poorly understood. The goal of this study was to use proteomics to relate temporal changes in mammary cell mitochondrial function during lactation to changes in the proteins that make up this organelle. The hypothesis tested was that changes in mammary cell mitochondrial biogenesis and function during lactation would be accounted for by coordinated changes in the proteins of the electron transport chain and that some of these proteins might be linked by their expression patterns to PPARGC1α and AMP kinase. The mitochondrial proteome was studied along with markers of mitochondrial biogenesis and function in mammary tissue collected from mice over the course of a single prolonged lactation cycle. Mammary tissue concentrations of AMP and ADP were increased ( P < 0.05) during early lactation and then declined with prolonged lactation. Similar changes were also observed for mitochondrial ATP synthesis activity, mitochondrial mass and DNA copy number. Analysis of the mammary cell mitochondrial proteome identified 244 unique proteins. Of these, only two proteins of the electron transport chain were found to increase during early lactation. In contrast, coordinated changes in numerous electron transport chain proteins were observed both during mid- and late lactation. There were six proteins that could be directly linked to PPARGC1α through network analysis. Abundance of PPARGC-1α and phosphorylation of AMP kinase was highest on day 2 postpartum. The results suggest that the increases in mammary mitochondria ATP synthesis activity during early lactation results from changes in only a limited number proteins. In addition, decreases in a handful of proteins linked to lipid oxidation could be temporally linked to decreases in PPARGC1α and phospho-AMP kinase suggesting potential roles for these proteins in coordinating mammary gland metabolism during early lactation.

scholarly journals Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1960
Author(s):  
K. Tanuj Sapra ◽  
Ohad Medalia
Keyword(s):  
Intermediate Filaments ◽  
Eukaryotic Cell ◽  
Coiled Coils ◽  
Cellular Functions ◽  
Mechanical Pressure ◽  
Mechanical Feature ◽  
Cellular Processes ◽  
Nuclear Lamins ◽  
Filament Networks ◽  
And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

scholarly journals Redox Regulation of Lipid Mobilization in Adipose Tissues

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1090
Author(s):  
Ursula Abou-Rjeileh ◽  
G. Andres Contreras
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Redox Regulation ◽  
Cellular Metabolism ◽  
Antioxidant Response ◽  
Redox Signaling ◽  
Nitrogen Species ◽  
Adipose Tissues ◽  
Lipid Mobilization ◽  
Cellular Processes

Lipid mobilization in adipose tissues, which includes lipogenesis and lipolysis, is a paramount process in regulating systemic energy metabolism. Reactive oxygen and nitrogen species (ROS and RNS) are byproducts of cellular metabolism that exert signaling functions in several cellular processes, including lipolysis and lipogenesis. During lipolysis, the adipose tissue generates ROS and RNS and thus requires a robust antioxidant response to maintain tight regulation of redox signaling. This review will discuss the production of ROS and RNS within the adipose tissue, their role in regulating lipolysis and lipogenesis, and the implications of antioxidants on lipid mobilization.

scholarly journals Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

2021 ◽  
Vol 22 (9) ◽  
pp. 4359
Author(s):  
Sara Martín-Villanueva ◽  
Gabriel Gutiérrez ◽  
Dieter Kressler ◽  
Jesús de la Cruz
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosome Assembly ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Precursor Proteins ◽  
Assembly Factors ◽  
Ubiquitin Moiety ◽  
And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

scholarly journals Validation of MicroRNA-188-5p Inhibition Power on Tumor Cell Proliferation in Papillary Thyroid Carcinoma

2020 ◽  
Vol 29 ◽  
pp. 096368972091830 ◽  
Author(s):  
Ping Zhou ◽  
Andrew Irving ◽  
Huifang Wu ◽  
Juan Luo ◽  
Johana Aguirre ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Tumor Cell ◽  
Cellular Proliferation ◽  
Tumor Cell Proliferation ◽  
Papillary Thyroid ◽  
Tumor Tissues ◽  
Potential Biomarker ◽  
And Function

Given the crucial role of microRNAs in the cellular proliferation of various types of cancers, we aimed to analyze the expression and function of a cellular proliferation-associated miR-188-5p in papillary thyroid carcinoma (PTC). Here we demonstrate that miR-188-5p is downregulated in PTC tumor tissues compared with the associated noncancerous tissues. We also validate that the miR-188-5p overexpression suppressed the PTC cancer cell proliferation. In addition, fibroblast growth factor 5 (FGF5) is observed to be downregulated in the PTC tumor tissues compared with the associated noncancerous tissues. Subsequently, FGF5 is identified as the direct functional target of miR-188-5p. Moreover, the silencing of FGF5 was found to inhibit PTC cell proliferation, which is the same pattern as miR-188-5p overexpression. These results suggest that miR-188-5p-associated silencing of FGF5 inhibits tumor cell proliferation in PTC. It also highlights the importance of further evaluating miR-188-5p as a potential biomarker and therapy target in PTC.

scholarly journals N-terminus oligomerization is conserved in intracellular calcium release channels

2014 ◽  
Vol 459 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Spyros Zissimopoulos ◽  
Jason Marsh ◽  
Laurence Stannard ◽  
Monika Seidel ◽  
F. Anthony Lai
Keyword(s):  
Structure Function ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Function Parameter ◽  
Calcium Release Channels ◽  
Cellular Processes ◽  
N Terminus ◽  
Intracellular Calcium Release ◽  
Ca2 Channels

Intracellular Ca2+ channels are of paramount importance for numerous cellular processes. In the present paper we report on a novel N-terminus intersubunit interaction, an essential structure–function parameter, which is conserved in both families of intracellular Ca2+ channels.

scholarly journals Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival

2006 ◽  
Vol 281 (43) ◽  
pp. 32841-32851 ◽  
Author(s):  
Brian DeBosch ◽  
Nandakumar Sambandam ◽  
Carla Weinheimer ◽  
Michael Courtois ◽  
Anthony J. Muslin
Keyword(s):  
Pressure Overload ◽  
Cardiac Metabolism ◽  
Cellular Protein ◽  
Growth Responses ◽  
Infarct Zone ◽  
Targeted Disruption ◽  
Cellular Processes ◽  
Ligand Stimulation ◽  
And Function

The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[3H]deoxyglucose uptake and metabolism. In contrast, akt2-/- mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2-/- mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2-/- hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival.

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