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#34608240   2021/10/04 To Up

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1 mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1 β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.
Kailiang Zhang, Rong Bao, Fengyuan Huang, Kevin Yang, Yishu Ding, Lothar Lauterboeck, Masasuke Yoshida, Qinqiang Long, Qinglin Yang

2139 related Products with: ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

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#34605675   2021/10/04 To Up

The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders?

Significance The mitochondrial oxidative phosphorylation (OXPHOS) system, comprising the electron transport chain and ATP synthase, generates membrane potential, drives ATP synthesis, governs energy metabolism, and maintains redox balance. OXPHOS dysfunction is associated with a plethora of diseases ranging from rare inherited disorders to common conditions including diabetes, cancer, neurodegenerative diseases, as well as aging. There has been great interest in studying regulators of OXPHOS. Among these, ATPase inhibitory factor 1 (IF1) is an endogenous inhibitor of ATP synthase that has long been thought to avoid the consumption of cellular ATP when ATP synthase acts as an ATP hydrolysis enzyme. Recent Advances Recent data indicates that IF1 inhibits ATP synthesis and is involved in a multitude of mitochondrial-related functions, such as mitochondrial quality control, energy metabolism, redox balance, and cell fate. IF1 also inhibits the ATPase activity of cell-surface ATP synthase, and it is used as a cardiovascular disease biomarker. Critical Issues Although recent data have led to a paradigm shift regarding IF1 functions, these have been poorly studied in entire organisms and in different organs. The understanding of the cellular biology of IF1 is, therefore, still limited. The aim of this review was to provide an overview of the current understanding of the role of IF1 in mitochondrial functions, health, and diseases. Future Directions Further investigations of IF1 functions at the cell, organ, and whole-organism levels and in different pathophysiological conditions will help decipher the controversies surrounding its involvement in mitochondrial function and could unveil therapeutic strategies in human pathology.
Emilia Gore, Thibaut Duparc, Annelise Genoux, Bertrand Perret, Souad Najib, Laurent O Martinez

2451 related Products with: The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders?

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#34477256   2021/09/03 To Up

Using principal component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.

Inflammation as a risk factor for preterm birth is well-established. The primary objective of this analysis was to examine whether individual cytokines versus a composite indicator of mid-pregnancy inflammation are significantly associated with risk for adverse birth outcomes.
Lauren S Keenan-Devlin, Madeleine Caplan, Alexa Freedman, Kristine Kuchta, William Grobman, Claudia Buss, Emma K Adam, Sonja Entringer, Gregory E Miller, Ann E B Borders

1460 related Products with: Using principal component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.

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#34298397   2021/07/20 To Up

IF1 inactivation attenuates experimental colitis through downregulation of neutrophil infiltration in colon mucosa.

IF1 is a mitochondrial protein involved in the regulation of ATP synthase activity. The role of IF1 remains to be established in inflammatory bowel diseases (IBD). In this study, we report that IF1 gene inactivation generated protection against IBD in the dextran sodium sulfate (DSS) model. IF1 gene knockout (IF1-KO) mice developed less severe colitis than the wild type (WT) mice as judged by parameters including disease activity index (DAI), body weight loss, inflammatory cytokines, leukocyte infiltration and bacterial invasion in the colon tissue. The intestinal barrier integrity was protected in the colon tissue of IF1-KO mice through a reduction in apoptosis and inflammasomal activity. The protection was abolished in the KO mice after substitution of the immune cells with the wild type cells following bone marrow transplantation. Depletion of neutrophils with anti-Gr-1 antibody abolished the protection from colitis in IF1-KO mice. Neutrophil number was decreased in the peripheral blood of IF1-KO mice, which was associated with a reduction in LC3A/B proteins in the KO neutrophils in Rapamycin-induced autophagy response. Inhibition of autophagy with the lysosome inhibitor Chloroquine (CQ) decreased the absolute number of neutrophils in WT mice and protected the mice from colitis. Taken together, these findings suggest that IF1 may contribute to the pathogenesis of IBD through acceleration of neutrophil autophagy. The activity is attenuated in the IF1-KO mice through reduction of autophagy in neutrophils leading to resistance to IBD.
Genshen Zhong, Jiaojiao Zhang, Ying Guo, Yichun Wang, Minna Wu, Jie Ren, Yuan Li, Xiaoying Zhang, Beiyan Zhou, Weidong Zhao, Yunwei Lou, Hui Wang, Jianping Ye

2405 related Products with: IF1 inactivation attenuates experimental colitis through downregulation of neutrophil infiltration in colon mucosa.

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#34262544   2021/06/28 To Up

A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines.

Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis.
Victor Barrenechea, Maryhory Vargas-Reyes, Miguel Quiliano, Pohl Milón

2558 related Products with: A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines.

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#34180254   2021/08/24 To Up

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues.

Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca homeostasis, all affecting insulin secretion. Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca influx was found to enhance GSIS, reflecting cytosolic Ca oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca and K channels) or the superimposed Ca release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states.
Petr Ježek, Blanka Holendová, Martin Jabůrek, Andrea Dlasková, Lydie Plecitá-Hlavatá

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#34161576   // To Up

The dynamic cycle of bacterial translation initiation factor IF3.

Initiation factor IF3 is an essential protein that enhances the fidelity and speed of bacterial mRNA translation initiation. Here, we describe the dynamic interplay between IF3 domains and their alternative binding sites using pre-steady state kinetics combined with molecular modelling of available structures of initiation complexes. Our results show that IF3 accommodates its domains at velocities ranging over two orders of magnitude, responding to the binding of each 30S ligand. IF1 and IF2 promote IF3 compaction and the movement of the C-terminal domain (IF3C) towards the P site. Concomitantly, the N-terminal domain (IF3N) creates a pocket ready to accept the initiator tRNA. Selection of the initiator tRNA is accompanied by a transient accommodation of IF3N towards the 30S platform. Decoding of the mRNA start codon displaces IF3C away from the P site and rate limits translation initiation. 70S initiation complex formation brings IF3 domains in close proximity to each other prior to dissociation and recycling of the factor for a new round of translation initiation. Altogether, our results describe the kinetic spectrum of IF3 movements and highlight functional transitions of the factor that ensure accurate mRNA translation initiation.
Jose A Nakamoto, Wilfredo Evangelista, Daria S Vinogradova, Andrey L Konevega, Roberto Spurio, Attilio Fabbretti, Pohl Milón

2002 related Products with: The dynamic cycle of bacterial translation initiation factor IF3.

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#33983919   2021/05/13 To Up

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.
Pau B Esparza-Moltó, Inés Romero-Carramiñana, Cristina Núñez de Arenas, Marta P Pereira, Noelia Blanco, Beatriz Pardo, Georgina R Bates, Carla Sánchez-Castillo, Rafael Artuch, Michael P Murphy, José A Esteban, José M Cuezva

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