Mechanisms of mitophagy in cellular homeostasis, physiology and pathology

Nature Cell Biology, Journal Year: 2018, Volume and Issue: 20(9), P. 1013 - 1022

Published: Aug. 20, 2018

Language: Английский

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Autophagy in kidney homeostasis and disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(9), P. 489 - 508

Published: July 23, 2020

Language: Английский

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Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2017, Volume and Issue: 8(3), P. 349 - 369

Published: April 21, 2017

Abstract Age is the most important risk factor for diseases. Mitochondria play a central role in bioenergetics and metabolism. In addition, several lines of evidence indicate impact mitochondria lifespan determination ageing. The best‐known hypothesis to explain ageing free radical theory, which proposes that cells, organs, organisms age because they accumulate reactive oxygen species (ROS) damage over time. as principle source intracellular ROS, are mainly formed at level complex I III respiratory chain. Dysfunctional generating less ATP have been observed various aged organs. Mitochondrial dysfunction comprises different features including reduced mitochondrial content, altered morphology, activity complexes electron transport chain, opening permeability transition pore, increased ROS formation. Furthermore, abnormalities quality control or defects dynamics also linked senescence. Among tissues affected by those with high‐energy demand thus high content. Therefore, present review focuses on process heart skeletal muscle. this article, we aspects discuss potential therapeutic strategies improve function. Finally, novel adipose tissue biology their involvement discussed.

Language: Английский

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Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

Science, Journal Year: 2017, Volume and Issue: 357(6350), P. 507 - 511

Published: July 14, 2017

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades investigation, the biological roles AMPK and its potential as drug target remain incompletely understood, largely because lack optimized pharmacological tools. We developed MK-8722, potent, direct, allosteric activator all 12 mammalian complexes. In rodents rhesus monkeys, MK-8722-mediated activation skeletal muscle induced robust, durable, insulin-independent glucose uptake glycogen synthesis, with resultant improvements glycemia no evidence hypoglycemia. These effects translated across species, including diabetic but manifested concomitant cardiac hypertrophy increased without apparent functional sequelae.

Language: Английский

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Repairing Mitochondrial Dysfunction in Disease

The Annual Review of Pharmacology and Toxicology, Journal Year: 2017, Volume and Issue: 58(1), P. 353 - 389

Published: Sept. 29, 2017

Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations mitochondrial function not only impact on metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by dysfunction have expanded from rare monogenic disorders in a strict sense to now include common polygenic diseases, metabolic, cardiovascular, neurodegenerative, neuromuscular diseases. This has led an intensive search new therapeutic preventive strategies aimed at invigorating exploiting key components biogenesis, redox dynamics, mitophagy, the unfolded protein response. As such, findings linking progression or outcome this ever-increasing list diseases stimulated discovery development first true drugs, which entering clinic discussed review.

Language: Английский

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Macrophage functions in lean and obese adipose tissue

Metabolism, Journal Year: 2017, Volume and Issue: 72, P. 120 - 143

Published: April 18, 2017

Language: Английский

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Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction

Circulation, Journal Year: 2019, Volume and Issue: 139(11), P. 1435 - 1450

Published: March 11, 2019

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance the hallmark of HFpEF and appears to be caused by both cardiac peripheral abnormalities arterial tree skeletal muscle. Mitochondrial can significantly contribute impaired oxygen utilization resulting exercise HFpEF. We review key aspects biology this organelle, clinical relevance mitochondrial function, methods that are currently available assess function humans, evidence supporting role for dysfunction pathophysiology also discuss as therapeutic target, some considerations design early-phase trials using agents specifically target improve symptoms patients HFpEF, ongoing

Language: Английский

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The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

Cell Metabolism, Journal Year: 2018, Volume and Issue: 28(3), P. 516 - 524.e7

Published: July 5, 2018

Language: Английский

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Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

Cancer Research, Journal Year: 2019, Volume and Issue: 79(4), P. 795 - 806

Published: Jan. 4, 2019

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor in mice subcutaneous tumors patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining PET 18fluoro-deoxyglucose (FDG) uptake 98 matched of NSCLC. also observed significant glycolytic gene signatures 513 NSCLC from The Cancer Genome Atlas database. secreted TNFα to promote glycolysis, whereas increased AMP-activated protein kinase peroxisome proliferator-activated receptor gamma coactivator 1-alpha facilitated hypoxia. Depletion by clodronate was sufficient abrogate hypoxia, thereby improving response depletion led increase programmed death-ligand 1 (PD-L1) expression cells as well T-cell infiltration tumors, resulting antitumor efficacy PD-L1 antibodies, which were otherwise completely ineffective. These data suggest can significantly alter metabolism, further complicating therapies, including immunotherapy. SIGNIFICANCE: findings show modulate hindering the anti-PD-L1

Language: Английский

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AMPK: Regulation of Metabolic Dynamics in the Context of Autophagy

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(12), P. 3812 - 3812

Published: Nov. 29, 2018

Eukaryotic cells have developed mechanisms that allow them to link growth and proliferation the availability of energy biomolecules. AMPK (adenosine monophosphate-activated protein kinase) is one most important molecular sensors in eukaryotic cells. activity able control a wide variety metabolic processes connecting cellular metabolism with availability. Autophagy an evolutionarily conserved catabolic pathway whose provides basic building blocks for synthesis new Given importance autophagic degradation production situations nutrient scarcity, it seems logical multiple links between signaling autophagy regulation. In this review, we will discuss diverse aspects metabolism, how modulates adapts energetic status. We explain AMPK-mediated mechanistically involved regulation both through specific phosphorylation autophagy-relevant proteins or by indirectly impacting additional regulators.

Language: Английский

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