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1.
Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity.
Rutter, GA, Georgiadou, E, Martinez-Sanchez, A, Pullen, TJ
Diabetologia. 2020;(10):1990-1998
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Abstract
All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed ('disallowed') in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1-7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell-beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion. Graphical abstract.
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2.
Effects of curcumin on mitochondria in neurodegenerative diseases.
Bagheri, H, Ghasemi, F, Barreto, GE, Rafiee, R, Sathyapalan, T, Sahebkar, A
BioFactors (Oxford, England). 2020;(1):5-20
Abstract
Neurodegenerative diseases (NDs) result from progressive deterioration of selectively susceptible neuron populations in different central nervous system (CNS) regions. NDs are classified in accordance with the primary clinical manifestations (e.g., parkinsonism, dementia, or motor neuron disease), the anatomic basis of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), and fundamental molecular abnormalities (e.g., mutations, mitochondrial dysfunction, and its related molecular alterations). NDs include the Alzheimer disease and Parkinson disease, among others. There is a growing evidence that mitochondrial dysfunction and its related mutations in the form of oxidative/nitrosative stress and neurotoxic compounds play major roles in the pathogenesis of various NDs. Curcumin, a polyphenol and nontoxic compound, obtained from turmeric, has been shown to have a therapeutic beneficial effect in various disorders especially on the CNS cells. It has been shown that curcumin has considerable neuro- and mitochondria-protective properties against broad-spectrum neurotoxic compounds and diseases/injury-associating NDs. In this article, we have reviewed the various effects of curcumin on mitochondrial dysfunction in NDs.
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3.
Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Suboptimal Mitochondrial Function: Assessment, Treatment and Classification Implications.
Anderson, G, Maes, M
Current topics in medicinal chemistry. 2020;(7):524-539
Abstract
The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.
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From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme.
Swenson, SA, Moore, CM, Marcero, JR, Medlock, AE, Reddi, AR, Khalimonchuk, O
Cells. 2020;(3)
Abstract
Heme is a ubiquitous and essential iron containing metallo-organic cofactor required for virtually all aerobic life. Heme synthesis is initiated and completed in mitochondria, followed by certain covalent modifications and/or its delivery to apo-hemoproteins residing throughout the cell. While the biochemical aspects of heme biosynthetic reactions are well understood, the trafficking of newly synthesized heme-a highly reactive and inherently toxic compound-and its subsequent delivery to target proteins remain far from clear. In this review, we summarize current knowledge about heme biosynthesis and trafficking within and outside of the mitochondria.
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Redox Signaling from Mitochondria: Signal Propagation and Its Targets.
Ježek, P, Holendová, B, Plecitá-Hlavatá, L
Biomolecules. 2020;(1)
Abstract
Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.
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Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease.
Li, R, Toan, S, Zhou, H
Aging. 2020;(7):6467-6485
Abstract
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 fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.
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Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity.
Chen, KY, Brychta, RJ, Abdul Sater, Z, Cassimatis, TM, Cero, C, Fletcher, LA, Israni, NS, Johnson, JW, Lea, HJ, Linderman, JD, et al
The Journal of biological chemistry. 2020;(7):1926-1942
Abstract
The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.
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Mitochondrial bioenergetics and redox dysfunctions in hypercholesterolemia and atherosclerosis.
Oliveira, HCF, Vercesi, AE
Molecular aspects of medicine. 2020;:100840
Abstract
In the first part of this review, we summarize basic mitochondrial bioenergetics concepts showing that mitochondria are critical regulators of cell life and death. Until a few decades ago, mitochondria were considered to play essential roles only in respiration, ATP formation, non-shivering thermogenesis and a variety of metabolic pathways. However, the concept presented by Peter Mitchell regarding coupling between electron flow and ATP synthesis through the intermediary of a H+ electrochemical potential leads to the recognition that the proton-motive force also regulates a series of relevant cell signalling processes, such as superoxide generation, redox balance and Ca2+ handling. Alterations in these processes lead to cell death and disease states. In the second part of this review, we discuss the role of mitochondrial dysfunctions in the specific context of hypercholesterolemia-induced atherosclerosis. We provide a literature analysis that indicates a decisive role of mitochondrial redox dysfunction in the development of atherosclerosis and discuss the underlying molecular mechanisms. Finally, we highlight the potential mitochondrial-targeted therapeutic strategies that are relevant for atherosclerosis.
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9.
Matrix Redox Physiology Governs the Regulation of Plant Mitochondrial Metabolism through Posttranslational Protein Modifications.
Møller, IM, Igamberdiev, AU, Bykova, NV, Finkemeier, I, Rasmusson, AG, Schwarzländer, M
The Plant cell. 2020;(3):573-594
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Abstract
Mitochondria function as hubs of plant metabolism. Oxidative phosphorylation produces ATP, but it is also a central high-capacity electron sink required by many metabolic pathways that must be flexibly coordinated and integrated. Here, we review the crucial roles of redox-associated posttranslational protein modifications (PTMs) in mitochondrial metabolic regulation. We discuss several major concepts. First, the major redox couples in the mitochondrial matrix (NAD, NADP, thioredoxin, glutathione, and ascorbate) are in kinetic steady state rather than thermodynamic equilibrium. Second, targeted proteomics have produced long lists of proteins potentially regulated by Cys oxidation/thioredoxin, Met-SO formation, phosphorylation, or Lys acetylation, but we currently only understand the functional importance of a few of these PTMs. Some site modifications may represent molecular noise caused by spurious reactions. Third, different PTMs on the same protein or on different proteins in the same metabolic pathway can interact to fine-tune metabolic regulation. Fourth, PTMs take part in the repair of stress-induced damage (e.g., by reducing Met and Cys oxidation products) as well as adjusting metabolic functions in response to environmental variation, such as changes in light irradiance or oxygen availability. Finally, PTMs form a multidimensional regulatory system that provides the speed and flexibility needed for mitochondrial coordination far beyond that provided by changes in nuclear gene expression alone.
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10.
Mitochondrial Calcium Regulation of Redox Signaling in Cancer.
Delierneux, C, Kouba, S, Shanmughapriya, S, Potier-Cartereau, M, Trebak, M, Hempel, N
Cells. 2020;(2)
Abstract
Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.