Mitochondria and Reactive Oxygen Species Contribute to Neurogenic Hypertension

Beyond its primary role as fuel generators, mitochondria are engaged in a variety of cellular processes, including redox homeostasis. Mitochondrial dysfunction, therefore, may have a profound impact on high-energy-demanding organs such as the brain. Here, we review the roles of mitochondrial biogenesis and bioenergetics, and their associated signaling in cellular redox homeostasis, and illustrate their contributions to the oxidative stress-related neural mechanism of hypertension, focusing on specific brain areas that are involved in the generation or modulation of sympathetic outflows to the cardiovascular system. We also highlight future challenges of research on mitochondrial physiology and pathophysiology.

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Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9971885 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Musbau Adewumi Akanji ◽

Damilare Emmanuel Rotimi ◽

Tobiloba Christiana Elebiyo ◽

Oluwakemi Josephine Awakan ◽

Oluyomi Stephen Adeyemi

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Redox Homeostasis ◽

Reactive Species ◽

Cellular Damage ◽

Cellular Mechanisms ◽

Cellular Redox ◽

Redox Imbalance ◽

Cellular Processes ◽

The Brain

Reactive species, such as those of oxygen, nitrogen, and sulfur, are considered part of normal cellular metabolism and play significant roles that can impact several signaling processes in ways that lead to either cellular sustenance, protection, or damage. Cellular redox processes involve a balance in the production of reactive species (RS) and their removal because redox imbalance may facilitate oxidative damage. Physiologically, redox homeostasis is essential for the maintenance of many cellular processes. RS may serve as signaling molecules or cause oxidative cellular damage depending on the delicate equilibrium between RS production and their efficient removal through the use of enzymatic or nonenzymatic cellular mechanisms. Moreover, accumulating evidence suggests that redox imbalance plays a significant role in the progression of several neurodegenerative diseases. For example, studies have shown that redox imbalance in the brain mediates neurodegeneration and alters normal cytoprotective responses to stress. Therefore, this review describes redox homeostasis in neurodegenerative diseases with a focus on Alzheimer’s and Parkinson’s disease. A clearer understanding of the redox-regulated processes in neurodegenerative disorders may afford opportunities for newer therapeutic strategies.

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S-Adenosylmethionine Deficiency and Brain Accumulation of S-Adenosylhomocysteine in Thioacetamide-Induced Acute Liver Failure

Nutrients ◽

10.3390/nu12072135 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2135

Author(s):

Anna Maria Czarnecka ◽

Wojciech Hilgier ◽

Magdalena Zielińska

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Redox Homeostasis ◽

Cerebral Function ◽

Total Glutathione ◽

Cellular Redox ◽

Therapeutic Value ◽

Transsulfuration Pathway ◽

Subsequent Hydrolysis ◽

The Brain

Background: Acute liver failure (ALF) impairs cerebral function and induces hepatic encephalopathy (HE) due to the accumulation of neurotoxic and neuroactive substances in the brain. Cerebral oxidative stress (OS), under control of the glutathione-based defense system, contributes to the HE pathogenesis. Glutathione synthesis is regulated by cysteine synthesized from homocysteine via the transsulfuration pathway present in the brain. The transsulfuration-transmethylation interdependence is controlled by a methyl group donor, S-adenosylmethionine (AdoMet) conversion to S-adenosylhomocysteine (AdoHcy), whose removal by subsequent hydrolysis to homocysteine counteract AdoHcy accumulation-induced OS and excitotoxicity. Methods: Rats received three consecutive intraperitoneal injections of thioacetamide (TAA) at 24 h intervals. We measured AdoMet and AdoHcy concentrations by HPLC-FD, glutathione (GSH/GSSG) ratio (Quantification kit). Results: AdoMet/AdoHcy ratio was reduced in the brain but not in the liver. The total glutathione level and GSH/GSSG ratio, decreased in TAA rats, were restored by AdoMet treatment. Conclusion: Data indicate that disturbance of redox homeostasis caused by AdoHcy in the TAA rat brain may represent a deleterious mechanism of brain damage in HE. The correction of the GSH/GSSG ratio following AdoMet administration indicates its therapeutic value in maintaining cellular redox potential in the cerebral cortex of ALF rats.

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Abstract 82: In Vivo Memri Reveals Persistent Activation of the Pvn by an Acute Systemic Angiotensin Ii Injection

Hypertension ◽

10.1161/hyp.60.suppl_1.a82 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Jasenka Zubcevic ◽

Pablo D Perez ◽

Jessica Marulanda Carvajal ◽

Mohan K Raizada ◽

Marcelo Febo

Keyword(s):

Neuronal Activity ◽

Spontaneously Hypertensive Rat ◽

Pressor Response ◽

Neuronal Response ◽

Neuronal Activation ◽

Brain Areas ◽

Neurogenic Hypertension ◽

Wistar Kyoto ◽

The Brain

Introduction: An overactive brain renin-angiotensin system is a major factor in the establishment of neurogenic hypertension in the spontaneously hypertensive rat (SHR). However, there is no concrete evidence to indicate that this is associated with enhanced neuronal activity in the brain. The objective here was to use the MRI to establish the effect of ANGII on neuronal activity in the autonomic brain areas. We propose that a single ANGII injection will cause a long-lasting neuronal response in the autonomic brain areas, which will be exaggerated in the SHR. Methods: In vivo basal and ANGII-evoked neuronal activity was measured in the Wistar-Kyoto (WKY) rat and the SHR using manganese-enhanced MRI (MEMRI) at 4.7Tesla. Rats were treated with manganese chloride (MnCl 2 30 mM solution, i.p .;16-20 hrs prior to the MRI), which labels active neurons. T 1 -weighted images were obtained 16-20 hrs after a single ANGII injection (0.32μg/kg i.p.). Coronal slice scans (caudally from end of the cerebellum towards the hypothalamus) were processed using itkSNAP, and data analyzed for normalized signal intensity. Results: Acute ANGII injection caused an immediate pressor response in the WKY (ΔSBP=∼20mmHg), normalizing within 2 hours. Despite this, ANGII evoked a persistent PVN neuronal activation, which was elevated by 22±4% in the WKY, and by 187±45% in the PVN of SHR. As a result, there was a ∼8.5fold increase in the ANGII-dependent neuronal activity in the PVN of SHR compared to WKY. Furthermore, there was a ∼2.5fold decrease in the NTS neuronal activity in the SHR compared to WKY. Conclusion: The present study shows for the first time the correlation between ANGII and autonomic neuronal activation. Even a single systemic ANGII injection results in a lasting effect on the brain. This is particularly apparent in the SHR, which exhibited an exaggerated neuronal response to the ANGII stimulus, reflected in the elevated PVN neuronal activation corresponding to the enhanced sympathetic drive, and in the depressed NTS activation corresponding to the dysfunction in the barorereflex processing. Thus, repeated pro-hypertensive stimuli in the autonomic brain areas may lead to pre-sympathetic neuronal plasticity, resulting in heightened sympathetic drive and hypertension.

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Time line of redox events in aging postmitotic cells

eLife ◽

10.7554/elife.00306 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 49

Author(s):

Nicolas Brandes ◽

Heather Tienson ◽

Antje Lindemann ◽

Victor Vitvitsky ◽

Dana Reichmann ◽

...

Keyword(s):

Redox Homeostasis ◽

Yeast Cells ◽

Free Radical Theory ◽

Radical Theory ◽

Cellular Redox ◽

Time Line ◽

Present Evidence ◽

Cellular Processes ◽

Theory Of Aging ◽

Substantial Drop

The precise roles that oxidants play in lifespan and aging are still unknown. Here, we report the discovery that chronologically aging yeast cells undergo a sudden redox collapse, which affects over 80% of identified thiol-containing proteins. We present evidence that this redox collapse is not triggered by an increase in endogenous oxidants as would have been postulated by the free radical theory of aging. Instead it appears to be instigated by a substantial drop in cellular NADPH, which normally provides the electron source for maintaining cellular redox homeostasis. This decrease in NADPH levels occurs very early during lifespan and sets into motion a cascade that is predicted to down-regulate most cellular processes. Caloric restriction, a near-universal lifespan extending measure, increases NADPH levels and delays each facet of the cascade. Our studies reveal a time line of events leading up to the system-wide oxidation of the proteome days before cell death.

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Impact of Sex and Age on the Mevalonate Pathway in the Brain: A Focus on Effects Induced by Maternal Exposure to Exogenous Compounds

Metabolites ◽

10.3390/metabo10080304 ◽

2020 ◽

Vol 10 (8) ◽

pp. 304 ◽

Cited By ~ 1

Author(s):

Claudia Tonini ◽

Marco Segatto ◽

Valentina Pallottini

Keyword(s):

Neurodevelopmental Disorders ◽

Mevalonate Pathway ◽

Maternal Exposure ◽

Cholesterol Homeostasis ◽

Brain Areas ◽

Cellular Processes ◽

Specific Manner ◽

Exogenous Compounds ◽

The Brain ◽

Age And Sex

The mevalonate pathway produces cholesterol and other compounds crucial for numerous cellular processes. It is well known that age and sex modulate this pathway in the liver. Recently, similar effects were also noted in different brain areas, suggesting that alterations of the mevalonate pathway are at the root of marked sex-specific disparities in some neurodevelopmental disorders related to disturbed cholesterol homeostasis. Here, we show how the mevalonate pathway is modulated in a sex-, age- and region-specific manner, and how maternal exposure to exogenous compounds can disturb the regulation of this pathway in the brain, possibly inducing functional alterations.

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Mitochondrial Dysfunction and Changes in High-Energy Compounds in Different Cellular Models Associated to Hypoxia: Implication to Schizophrenia

Scientific Reports ◽

10.1038/s41598-019-53605-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Luiz Felipe Souza e Silva ◽

Mariana Dutra Brito ◽

Jéssica Mayumi Camargo Yuzawa ◽

Tatiana Rosado Rosenstock

Keyword(s):

Redox Homeostasis ◽

Atp Synthesis ◽

Redox System ◽

High Energy ◽

Spontaneously Hypertensive ◽

Cellular Models ◽

Nadh Ratio ◽

Intrauterine Hypoxia ◽

Lactate Levels ◽

The Brain

AbstractSchizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. Considering that numerous neural mechanisms depends on energetic supply (ATP synthesis), the maintenance of mitochondrial metabolism is essential to keep cellular balance and survival. Therefore, in the present work, we evaluated functional parameters related to mitochondrial function, namely calcium levels, mitochondrial membrane potential, redox homeostasis, high-energy compounds levels and oxygen consumption, in astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR) animals exposed both to chemical and gaseous hypoxia. We show that astrocytes after hypoxia presented depolarized mitochondria, disturbances in Ca2+ handling, destabilization in redox system and alterations in ATP, ADP, Pyruvate and Lactate levels, in addition to modification in NAD+/NADH ratio, and Nfe2l2 and Nrf1 expression. Interestingly, intrauterine hypoxia also induced augmentation in mitochondrial biogenesis and content. Altogether, our data suggest that hypoxia can induce mitochondrial deregulation and a decrease in energy metabolism in the most prevalent cell type in the brain, astrocytes. Since SHR are also considered an animal model of SZ, our results can likewise be related to their phenotypic alterations and, therefore, our work also allow an increase in the knowledge of this burdensome disorder.

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Neurodegenerative Disorders: Spotlight on Sphingolipids

International Journal of Molecular Sciences ◽

10.3390/ijms222111998 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11998

Author(s):

Frida Mandik ◽

Melissa Vos

Keyword(s):

Neurodegenerative Diseases ◽

Energy Production ◽

Gene Mutations ◽

Head Group ◽

Bioactive Lipids ◽

Brain Areas ◽

Causative Gene ◽

Cellular Processes ◽

Progressive Loss ◽

The Brain

Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson’s disease.

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Aetiologies and anatomy of confabulation

10.1093/oso/9780198789680.003.0004 ◽

2017 ◽

Author(s):

Armin Schnider

Keyword(s):

Brain Damage ◽

Limbic Encephalitis ◽

Artery Aneurysm ◽

Anterior Communicating Artery ◽

Brain Areas ◽

Anatomical Basis ◽

Korsakoff Syndrome ◽

Hypoxic Brain ◽

Degenerative Dementia ◽

The Brain

What diseases cause confabulations and which are the brain areas whose damage is responsible? This chapter reviews the causes, both historic and present, of confabulations and deduces the anatomo-clinical relationships for the four forms of confabulation in the following disorders: alcoholic Korsakoff syndrome, traumatic brain injury, rupture of an anterior communicating artery aneurysm, posterior circulation stroke, herpes and limbic encephalitis, hypoxic brain damage, degenerative dementia, tumours, schizophrenia, and syphilis. Overall, clinically relevant confabulation is rare. Some aetiologies have become more important over time, others have virtually disappeared. While confabulations seem to be more frequent after anterior brain damage, only one form has a distinct anatomical basis.

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Mitochondria-Targeted Ratiometric Fluorescent Imaging of Cysteine

The Analyst ◽

10.1039/d1an00758k ◽

2021 ◽

Author(s):

Ya-Nan Wei ◽

Bo Lin ◽

Yang Shu ◽

Jian-Hua Wang

Keyword(s):

Reactive Oxygen Species ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Fluorescent Imaging ◽

Oxygen Species ◽

Cellular Redox ◽

Critical Part ◽

Physiological Processes

As an indispensable biothiol, cysteine (Cys) plays a critical part in cellular redox homeostasis, pathological and physiological processes. One of the main sources of reactive oxygen species (ROS) in human...

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(Ascorb)ing Pb Neurotoxicity in the Developing Brain

Antioxidants ◽

10.3390/antiox9121311 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1311

Author(s):

Faraz Ahmad ◽

Ping Liu

Keyword(s):

Ascorbic Acid ◽

Animal Studies ◽

Redox Homeostasis ◽

Special Role ◽

Developmental Exposure ◽

Brain Functions ◽

Brain States ◽

Pb Exposure ◽

The Brain ◽

Potent Therapeutic Agent

Lead (Pb) neurotoxicity is a major concern, particularly in children. Developmental exposure to Pb can alter neurodevelopmental trajectory and has permanent neuropathological consequences, including an increased vulnerability to further stressors. Ascorbic acid is among most researched antioxidant nutrients and has a special role in maintaining redox homeostasis in physiological and physio-pathological brain states. Furthermore, because of its capacity to chelate metal ions, ascorbic acid may particularly serve as a potent therapeutic agent in Pb poisoning. The present review first discusses the major consequences of Pb exposure in children and then proceeds to present evidence from human and animal studies for ascorbic acid as an efficient ameliorative supplemental nutrient in Pb poisoning, with a particular focus on developmental Pb neurotoxicity. In doing so, it is hoped that there is a revitalization for further research on understanding the brain functions of this essential, safe, and readily available vitamin in physiological states, as well to justify and establish it as an effective neuroprotective and modulatory factor in the pathologies of the nervous system, including developmental neuropathologies.

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