New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury

Angiogenesis, Journal Year: 2020, Volume and Issue: 23(3), P. 299 - 314

Published: April 3, 2020

Language: Английский

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Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia–reperfusion injury

Acta Pharmaceutica Sinica B, Journal Year: 2020, Volume and Issue: 10(10), P. 1866 - 1879

Published: April 9, 2020

Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion (I/R) injury. quality control (MQC) mechanisms, series of adaptive responses that preserve mitochondrial structure and function, ensure cardiomyocyte survival function after I/R MQC includes fission, fusion, mitophagy mitochondria-dependent cell death. The interplay among these linked pathological changes such as redox imbalance, calcium overload, energy metabolism disorder, signal transduction arrest, the unfolded protein response endoplasmic reticulum stress. Excessive fission an early marker Reduced fusion has been observed in stressed cardiomyocytes correlates with dysfunction depression. Mitophagy allows autophagosomes selectively degrade poorly structured mitochondria, thus maintaining network fitness. Nevertheless, abnormal maladaptive Although mitochondria serve fuel source heart by continuously producing adenosine triphosphate, they also stimulate death inducing apoptosis or necroptosis reperfused myocardium. Therefore, defects may determine fate cardiomyocytes. In this review, we summarize regulatory mechanisms effects myocardial injury, highlighting potential targets for clinical management reperfusion.

Language: Английский

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Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control

Redox Biology, Journal Year: 2020, Volume and Issue: 38, P. 101777 - 101777

Published: Nov. 1, 2020

The death of cardiomyocytes either through apoptosis or necroptosis is the pathological feature cardiac ischemia-reperfusion (I/R) injury. Phosphoglycerate mutase 5 (PGAM5), a mitochondrially-localized serine/threonine-protein phosphatase, functions as novel inducer necroptosis. However, intense debate exists regarding effect PGAM5 on I/R-related cardiomyocyte death. Using cardiac-specific knockout (PGAM5CKO) mice, we comprehensively investigated precise contribution and molecular mechanism in Our data showed that both transcription expression were upregulated reperfused myocardium. Genetic ablation suppressed I/R-mediated but failed to prevent activation, result went along with improved heart function decreased inflammation response. Regardless status, mitophagy-related cell was not apparent following I/R. Under physiological conditions, overexpression primary sufficient induce rather than apoptosis. At sub-cellular levels, deficiency increased mitochondrial DNA copy number transcript normalized respiration, repressed ROS production, prevented abnormal mPTP opening upon Molecular investigation demonstrated deletion interrupted DrpS637 dephosphorylation abolish I/R-induce Drp1S616 phosphorylation, resulting partial inhibition fission. In addition, declining Mfn2 OPA1 levels restored PGAM5CKO Nevertheless, depletion did rescue mitophagy I/R conclusion, our results provide an insight into specific role working driving imposing quality control

Language: Английский

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The Complex Interplay between Mitochondria, ROS and Entire Cellular Metabolism

Antioxidants, Journal Year: 2022, Volume and Issue: 11(10), P. 1995 - 1995

Published: Oct. 8, 2022

Besides their main function for energy production in form of ATP processes oxidative phosphorylation (OxPhos), mitochondria perform many other important cellular functions and participate various physiological that are congregated. For example, considered to be one the sources reactive oxygen species (ROS) therefore they actively regulation redox ROS signaling. These organelles also play a crucial role Ca2+ signaling homeostasis. The mitochondrial OxPhos strongly cell/tissue specific can heterogeneous even within same cell, due existence subpopulations with distinct functional structural properties. However, interplay between different is not fully understood. may change as response changes metabolism (signaling in). On hand, several factors feedback signals from influence entire cell physiology out). Numerous interactions rest cytoskeletal proteins, endoplasmic reticulum (ER) elements have been demonstrated, these could metabolism. This review highlights physiology, including mitochondria.

Language: Английский

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Assembly of Genetically Engineered Ionizable Protein Nanocage-based Nanozymes for Intracellular Superoxide Scavenging

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 28, 2025

Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employ genetic engineering strategy generate ionizable ferritin nanocages (iFTn), enabling escape from endo-lysosomes and entry into the cytoplasm. Specifically, repeated Histidine-Histidine-Glutamic acid (9H2E) sequences are genetically incorporated outer surface of human heavy chain FTn, followed by assembly various chain-like nanostructures via two-armed polyethylene glycol (PEG). Utilizing endosome-escaping ability, design iFTn-based tetrameric cascade nanozymes with high superoxide dismutase- catalase-mimicking activities. The vivo protective effects these against cardiac injury demonstrated female mouse models ischemia-reperfusion (IR). RNA-sequencing analysis highlight crucial modulating anions-, hydrogen peroxide- mitochondrial functions-relevant genes IR injured tissue. These engineered protein nanocarriers provide opportunities developing drug delivery systems. promising treating diseases regulating cytotoxic radicals, but mediating radicals have been limited endolysosomal entrapment, Here, authors report create nanocage-based able endolysosomes enter

Language: Английский

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SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Molecular Therapy — Nucleic Acids, Journal Year: 2020, Volume and Issue: 22, P. 696 - 707

Published: Sept. 16, 2020

Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target cardioprotection. In this study, we investigated molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, analyzed microvascular protective effects sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) on reperfused heart and examined role SERCA regulating mitochondrial quality control endothelial cells (CMECs). Our data showed that overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, improves endothelium-dependent vascular relaxation. vitro experiments demonstrated viability, barrier integrity, cytoskeleton assembly CMECs. Mitochondrial control, including fusion, mitophagy, bioenergetics, biogenesis, were disrupted by but restored overexpression. also inhibiting calcium overload, inactivating xanthine oxidase (XO), reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration exogenous XO or channel agonist abolished offset beneficial after injury. These findings indicate may be an effective approach targeting calcium/XO/ROS signaling preserving control.

Language: Английский

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Mitochondria as a therapeutic target for cardiac ischemia‑reperfusion injury (Review)

International Journal of Molecular Medicine, Journal Year: 2020, Volume and Issue: 47(2), P. 485 - 499

Published: Dec. 16, 2020

Acute myocardial infarction is the leading cause of cardiovascular‑related mortality and chronic heart failure worldwide. As regards treatment, reperfusion ischemic tissue generates irreversible damage to myocardium, which termed 'cardiac ischemia‑reperfusion (IR) injury'. Due large number mitochondria in cardiomyocytes, an increasing studies have focused on roles IR injury. The primary causes injury are reduced oxidative phosphorylation during hypoxia increased production reactive oxygen species (ROS), together with insufficient elimination these following reperfusion. includes oxidation DNA, incorrect modifications proteins, disruption mitochondrial membrane respiratory chain, loss potential (∆Ψm), Ca2+ overload, permeability transition pore formation, swelling mitochondria, ultimately, cardiomyocyte necrosis. present review article discusses molecular mechanisms injury, summarizes metabolic dynamic changes occurring response stress. strongly recommended as a target for development therapeutic agents; however, appropriate use agents remains challenge.

Language: Английский

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Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Aging, Journal Year: 2020, Volume and Issue: 12(7), P. 6467 - 6485

Published: March 26, 2020

Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD).The mitochondria are the major sites of β-oxidation, a catabolic process by which acids broken down.The quality control (MQC) system includes fission, fusion, mitophagy redox regulation, is essential for maintenance functionality structural integrity mitochondria.Excessive uncontrolled production reactive oxygen species (ROS) damages components, including membranes, proteins DNA (mtDNA), triggers pathway apoptosis.The some damaged can be restored fusion with normally functioning mitochondria, but when severely damaged, segregated from remaining functional network through fission eventually degraded via autophagy, also called as mitophagy.In this review, we describe functions mechanisms oxidative stress development progression NAFLD.

Language: Английский

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Mitochondria Lead the Way: Mitochondrial Dynamics and Function in Cellular Movements in Development and Disease

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 9

Published: Feb. 2, 2022

The dynamics, distribution and activity of subcellular organelles are integral to regulating cell shape changes during various physiological processes such as epithelial formation, migration morphogenesis. Mitochondria famously known the powerhouse play an important role in buffering calcium, releasing reactive oxygen species key metabolites for activities a eukaryotic cell. Mitochondrial dynamics morphology regulate these functions their regulation is, turn, crucial morphogenetic processes. In this review, we evaluate recent literature which highlights mitochondrial division, tissue morphogenesis organism development disease. general, find that is regulated or translocation sites active Often, released locally molecules buffered by mitochondria roles signaling pathways motivate shape, activity. We conclude mechanistic analysis interactions between morphology, activity, across animal-based model systems holds deciphering common principles interaction.

Language: Английский

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An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives

Cells, Journal Year: 2022, Volume and Issue: 11(7), P. 1165 - 1165

Published: March 30, 2022

Cardiovascular disease is the leading cause of death in western countries. Among cardiovascular diseases, myocardial infarction represents a life-threatening condition predisposing to development heart failure. In recent decades, much effort has been invested studying molecular mechanisms underlying and progression ischemia/reperfusion (I/R) injury post-ischemic cardiac remodeling. These include metabolic alterations, ROS overproduction, inflammation, autophagy deregulation mitochondrial dysfunction. This review article discusses most evidence regarding basis ischemic new potential therapeutic interventions for boosting cardioprotection attenuating

Language: Английский

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