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1.
Insight of the role of mitochondrial calcium homeostasis in hepatic insulin resistance.
Dong, Z, Yao, X
Mitochondrion. 2022;:128-138
Abstract
Due to the rapid rise in the prevalence of chronic metabolic disease, more and more clinicians and basic medical researchers focus their eyesight on insulin resistance (IR), an early and central event of metabolic diseases. The occurrence and development of IR are primarily caused by excessive energy intake and reduced energy consumption. Liver is the central organ that controls glucose homeostasis, playing a considerable role in systemic IR. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are being blamed as the direct reason for the development of IR. Mitochondrial Ca2+ plays a fundamental role in maintaining proper mitochondrial function and redox stability. The maintaining of mitochondrial Ca2+ homeostasis requires the cooperation of ion channels in the inner and outer membrane of mitochondria, such as mitochondrial calcium uniporter complex (MCUC) and voltage-dependent anion channels (VDACs). In addition, the crosstalk between the endoplasmic reticulum (ER), lysosome and plasma membrane with mitochondria is also significant for mitochondrial calcium homeostasis, which is responsible for an efficient network of cellular Ca2+ signaling. Here, we review the recent progression in the research about the regulation factors for mitochondrial Ca2+ and how the dysregulation of mitochondrial Ca2+ homeostasis is involved in the pathogenesis of hepatic IR, providing a new perspective for further exploring the role of ion in the onset and development of IR.
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2.
Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.
Geisberger, S, Bartolomaeus, H, Neubert, P, Willebrand, R, Zasada, C, Bartolomaeus, T, McParland, V, Swinnen, D, Geuzens, A, Maifeld, A, et al
Circulation. 2021;(2):144-158
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Abstract
BACKGROUND Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. METHODS Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichiacoli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.
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Regulation of Cytochrome c Oxidase by Natural Compounds Resveratrol, (-)-Epicatechin, and Betaine.
Lee, I
Cells. 2021;(6)
Abstract
Numerous naturally occurring molecules have been studied for their beneficial health effects. Many compounds have received considerable attention for their potential medical uses. Among them, several substances have been found to improve mitochondrial function. This review focuses on resveratrol, (-)-epicatechin, and betaine and summarizes the published data pertaining to their effects on cytochrome c oxidase (COX) which is the terminal enzyme of the mitochondrial electron transport chain and is considered to play an important role in the regulation of mitochondrial respiration. In a variety of experimental model systems, these compounds have been shown to improve mitochondrial biogenesis in addition to increased COX amount and/or its enzymatic activity. Given that they are inexpensive, safe in a wide range of concentrations, and effectively improve mitochondrial and COX function, these compounds could be attractive enough for possible therapeutic or health improvement strategies.
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4.
Mitochondrial proton leaks and uncoupling proteins.
Nicholls, DG
Biochimica et biophysica acta. Bioenergetics. 2021;(7):148428
Abstract
Non-shivering thermogenesis in brown adipose tissue is mediated by uncoupling protein 1 (UCP1), which provides a carefully regulated proton re-entry pathway across the mitochondrial inner membrane operating in parallel to the ATP synthase and allowing respiration, and hence thermogenesis, to be released from the constraints of respiratory control. In the 40 years since UCP1 was first described, an extensive, and frequently contradictory, literature has accumulated, focused on the acute physiological regulation of the protein by fatty acids, purine nucleotides and possible additional factors. The purpose of this review is to examine, in detail, the experimental evidence underlying these proposed mechanisms. Emphasis will be placed on the methodologies employed and their relation to the physiological constraints under which the protein functions in the intact cell. The nature of the endogenous, UCP1-independent, proton leak will also be discussed. Finally, the troubled history of the putative novel uncoupling proteins, UCP2 and UCP3, will be evaluated.
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5.
Mitochondrial dysfunction as a critical event in the pathophysiology of bipolar disorder.
Scaini, G, Andrews, T, Lima, CNC, Benevenuto, D, Streck, EL, Quevedo, J
Mitochondrion. 2021;:23-36
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Abstract
The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca2+ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.
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[The Molecular Mechanisms of Mitochondrial Calcium Uptake by Calcium Uniporter].
Yamamoto, T
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2021;(4):491-499
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Abstract
Mitochondria play a role as intracellular calcium stores as well as energy conversion functions. Excessive calcium accumulation in mitochondria induces cell death and induces diseases such as ischemia-reperfusion injury. Mitochondrial calcium uptake is considered to be mediated by calcium uniporters, which have attracted much attention as potential drug targets. Although calcium uniporter was shown to function as an ion channel, the molecular mechanisms have long been unclear. In this decade, the molecular composition of the calcium uniporter complex was discovered; the calcium uniporter consists of the 7 subunits. Each subunit has no structural similarity to other Ca ion channels; thus, the novel molecular mechanism of the Ca2+ uptake by calcium uniporter is of interest. Although calcium uniporter is conserved in human to warm, yeast lack mitochondrial calcium uptake activity. In the previous study, various subunits of mammalian calcium uniporter were expressed in the yeast mitochondria. As a result, although the expression of each subunit alone did not affect on the mitochondrial calcium uptake activity, the co-expression of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) enabled to reconstitute calcium uptake activity in yeast mitochondria. This indicated that MCU and EMRE are key factors of the calcium uptake activity in mitochondria. This yeast reconstitution technique has also enabled us to perform detailed structure-function analysis of the MCU and EMRE. In this paper, we will discuss the molecular mechanism of Ca2+ uptake and the prospects for drug discovery.
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Reviving mitochondrial bioenergetics: A relevant approach in epilepsy.
Singh, S, Singh, TG, Rehni, AK, Sharma, V, Singh, M, Kaur, R
Mitochondrion. 2021;:213-226
Abstract
Epileptogenesis is most commonly associated with neurodegeneration and a bioenergetic defect attributing to the fact that mitochondrial dysfunction plays a key precursor for neuronal death. Mitochondria are the essential organelle of neuronal cells necessary for certain neurophysiological processes like neuronal action potential activity and synaptic transmission. The mitochondrial dysfunction disrupts calcium homeostasis leading to inhibitory interneuron dysfunction and increasing the excitatory postsynaptic potential. In epilepsy, the prolonged repetitive neuronal activity increases the excessive demand for energy and acidosis in the brain further increasing the intracellular calcium causing neuronal death. Similarly, the mitochondrial damage also leads to the decline of energy by dysfunction of the electron transport chain and abnormal production of the ROS triggering the apoptotic neuronal death. Thus, the elevated level of cytosolic calcium causes the mitochondria DNA damage coinciding with mtROS and releasing the cytochrome c binding to Apaf protein further initiating the apoptosis resulting in epileptic encephalopathies. The various genetic and mRNA studies of epilepsy have explored the various pathogenic mutations of genes affecting the mitochondria functioning further initiating the neuronal excitotoxicity. Based on the results of previous studies, the recent therapeutic approaches are targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria and hold great promise to attenuate epileptogenesis. Therefore, the current review emphasizes the emerging insights to uncover the relation between mitochondrial dysfunction and ROS generation contributing to mechanisms underlying epileptic seizures.
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Aging of Brain Related with Mitochondrial Dysfunctions.
Dhote, V, Samundre, P, Ganeshpurkar, A, Upaganlawar, A
Current drug targets. 2021;(14):1668-1687
Abstract
Advancing age presents a major challenge for the elderly population in terms of quality of life. The risk of cognitive impairment, motor in-coordination, and behavioral inconsistency due to neuronal damage is relatively higher in aging individuals of society. The brain, through its structural and functional integrity, regulates vital physiological events; however, the susceptibility of the brain to aging-related disturbances signals the onset of neurodegenerative diseases. Mitochondrial dysfunctions impair bioenergetic mechanism, synaptic plasticity, and calcium homeostasis in the brain, thus sufficiently implying mitochondria as a prime causal factor in accelerating aging-related neurodegeneration. We have reviewed the fundamental functions of mitochondria in a healthy brain and aimed to address the key issues in aging-related diseases by asking: 1) What goes wrong with mitochondria in the aging brain? 2) What are the implications of mitochondrial damage on motor functions and psychiatric symptoms? 3) How environmental chemicals and metabolic morbidities affect mitochondrial functions? Further, we share insights on opportunities and pitfalls in drug discovery approaches targeting mitochondria to slow down the progression of aging and related neurodegenerative diseases.
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The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease.
Varughese, JT, Buchanan, SK, Pitt, AS
Cells. 2021;(7)
Abstract
The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson's disease (PD), Friedreich's ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases.
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Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria.
Otasevic, V, Vucetic, M, Grigorov, I, Martinovic, V, Stancic, A
Oxidative medicine and cellular longevity. 2021;:5537330
Abstract
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.