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- Volume 20, Issue 35, 2014
Current Pharmaceutical Design - Volume 20, Issue 35, 2014
Volume 20, Issue 35, 2014
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Editorial (Thematic Issue: Mitochondrial Biogenesis: Pharmacological Approaches)
More LessOrganelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber’s hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh’s syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1α, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or α-lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, α-syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and α-lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. In order to find effective treatments to these up to date uncured diseases, comprehensive studies are therefore necessary on the control mechanisms of mitochondrial biogenesis, on the dynamic mitochondrial balance (fusion, fission, mitophagy and trafficking) and on the potential crosstalk among different biological processes, as expressed by the authors, along with the development of novel animal models to appropriately study this mitochondriogenesis. A switch in bioenergetics is necessary for cancer development. Thus the control of mitochondrial bioenergetics and dynamics could be useful as potential interventions on cancer treatments. Pilar Roca, Jorge Sastre-Serra, Mercedes Nadal-Serrano, Daniel Gabriel Pons, Mª del Mar Blanquer-Rosselló and Jordi Oliver (Institut d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Spain) [8] describe the regulation of estrogen receptors, their implication on breast cancer, on mitochondrial biogenesis, mitochondrial function, and ROS production. It deeply reviews the group of natural compounds intimately related to estrogen receptors, flavonoids, and their application in cancer treatment and research, their action mechanisms, etc. giving an emphasis on the differences found in the response depending on the doses, timing, absorption, metabolism and hormonal status for the design of new strategies to treat breast cancer. In the search of new targets for therapies based on targeting mitochondrial biogenesis it is of extreme importance to understand the pathways involved as well as the mediators that promote these signaling pathways. Fabian Sanchis-Gomar, José Luis García-Giménez, Mari Carmen Gómez-Cabrera and Federico V. Pallardó (Department of Physiology, University of Valencia / CIBERER / INCLIVA, Spain) [9] make a broad review on the current knowledge in this field, as well as about the diseases which course with alterations on the mitochondrial biogenesis pathways. Although the knowledge on specific treatments based on mitochondriogenesis is still poor, several drugs that are currently in the market present features potentially useful to trigger mitochondriogenesis for the treatment of specific diseases. This review compiles most of them, making an emphasis on the observed side effects of these drugs and the lack of selectivity of these strategies due to the fact that mitochondriogenesis is a ubiquitous phenomenon. Far from being a backward, this may constitute a challenge for designing more tissue-specific therapeutic approaches. The study of mitochondrial biogenesis is especially complex, due to the endosymbiotic evolutionary origin of this organelle. Mitochondria are the most complex and unique organelles: eukaryotic and prokaryotic mechanisms coexist, they possess an inner and an outer membrane, own small genome and they suffer continuous fusion and fission events. Moreover, along with endosymbiosis, novel mitochondrial biogenesis pathways have evolved [1]. In order to extend our knowledge about underlying mechanisms via which mitochondriogenesis in different tissues is induced, it is crucial to use the proper techniques to measure mitochondrial mass. In living cells, the regulation of mitochondrial content or mitochondrial mass depends on the subtle balance between mitochondrial biogenesis, mitochondrial degradation (mitophagy) and mitochondrial dynamics (fusion, fission). Karl J. Tronstad, Marco Nooteboom, Linn I. H. Nilsson, Julie Nikolaisen, Maciek Sokolewicz, Sander Grefte, Ina K.N. Pettersen, Sissel Dyrstad, Fredrik Hoel, Peter H.G.M. Willems and Werner J.H. Koopman (Department of Biomedicine, University of Bergen, Norway / Department of Biochemistry Radboud University Medical Centre, The Netherlands) [10] describe the mechanism that maintains this equilibrium and the available techniques to quantify mitochondrial morphology and content. After reviewing the advantages and disadvantages of the most common techniques and strategies (measuring oxygen consumption, biochemical biomarkers or by electron microscopy), we can find in this work a deep analysis on fluorescence microscopy for the detection of mitochondrial content, its visualization, quantitation and interpretation of results both in 2D and in 3D imaging, along with available software and strategies developed by this group and others. This work can be of great help at the time to choose a technique to study mitochondrial biogenesis in a specific cell type. In addition, we can also find a table with several drugs known to affect mitochondriogenesis. Free radicals have been widely considered as harmful for the cellular structures and promoters of senescence. However, they also act as second messengers by triggering signals which induce gene expression. Indeed, endogenous free radicals can trigger mitochondriogenesis. Hagir B. Suliman, and Claude A. Piantadosi (Departments of Anesthesiology, Duke Cancer Institute, Medicine and Pathology, Duke University Medical Center, USA) [11] broadly review the effect of these free radicals on mitochondriogenesis during inflammation. In periods of active inflammation, due to an acute tissue damage, mitochondria are frequently damaged by oxidative and nitrosative stress. The elevated levels of endogenous free radicals trigger mitochondriogenesis and mitophagy in a compensatory manner. This is the case of the NO/cGMP/PGC-1α axis, the CO/HO-1 system and the HS2/Akt/NRF-1/-2 axis. Several well known drugs can interact with those and other signaling pathways to induce mitochondriogenesis like NO donors, CO releasing molecules, triterpenoids, erythropoietin, thiazolidinedione drugs, metformin, AICAR and several natural compounds (including nutrients and scavengers). Thus inducing mitochondrial biogenesis and quality control represents a potential valuable approach for the development of new therapies for those diseases which course with mitochondrial damage and/or inflammation. Much attention has been attracted by recent discoveries pointing out mitochondrial biogenesis as a key process on lifespan extension, e.g. similar molecules and pathways as well as similar interventions have been found to be common in both processes. Enzo Nisoli and Alessandra Valerio (Center for Study and Research on Obesity / Department of Medical Biotechnology and Translational Medicine, University of Milan / Department of Molecular and Translational Medicine, University of Brescia, Italy) [12] review the contribution of mitochondria and other organelles on aging and anti aging-strategies, pointing out the interplay between organelles as a potential target for the design of new therapeutic interventions against age-related diseases and to increase life- and healthspan. Some interventions include the nonpharmacological control of mitochondrial biogenesis and dynamics by caloric restriction, endurance exercise and dietary supplementation with a mixture of essential amino acids enriched in branched-chain amino acids (BCAAs). However new pharmacological strategies seem to be very promising such as the new small SIRT1 activators (SRT1720, SRT2183, SRT1460), other sirtuin activators such as oxazolo[4,4-b]pyridine and imidazol[1,2-b]thiazole derivatives, the small GSK-3 inhibitors SB216763, and ZLN005 (with unknown action mechanism) or eNOS activators such as the AVE compounds. It is worth highlighting the latest evidence that points out low concentrations of free radicals as promoters of mitochondrial biogenesis and lifespan extension. These discoveries are closely associated with the new concept of mitochondrial hormesis or mitohormesis. Hormesis is the term that defines a positive action in response to a mild stress that would be detrimental for the cell or the organism if it would be administered at higher intensities or concentrations [13]. There are many examples of evolutionary conserved processes in which the exposure of a cell or an organism to a low dose of one stressor triggers an adaptive response that protects the cell or the organism from a moderate or severe level of stress. Indeed, free radicals, classically considered as deleterious, have been shown to act as second messengers at low concentrations to trigger different signaling pathways. Several terms have been used by the scientific community such as autoprotection, heteroprotection, preconditioning, adaptive responses, compensatory mechanisms, hormesis, xenohormesis, etc. In the same way, a wide range of terms have been used to describe the shape of the dose-response curve obtained at low concentrations such as diphasic, biphasic, bitonic, bell-shaped, Ushaped, inverted-U-shaped, etc. [14]. Although the information about this issue is diluted by the different terminology, these kinds of phenomena have been widely observed. Considering specifically mitochondria, it has been observed that a modest production of free radicals by this organelle can act as second messengers to trigger mitochondriogenesis [15]. Mitohormesis is therefore the beneficial effect produced in the cell due to the moderate production of free radicals by the mitochondria and is closely related to the phenomena of mitochondrial biogenesis and lifespan extension. This special issue tries to cover most of the current knowledge about the pharmacological approaches to trigger mitochondriogenesis, the signaling pathways involved, their regulation and the implication of mitochondriogenesis on several diseases. However, this field is still in its infancy. More research needs to be done on mitochondrial biogenesis not only with the goal of healing certain pathologies but also to find, if not the legendary Fountain of Youth, maybe an approach to reduce suffering and morbidity at advanced ages.
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Metabolic Reprogramming of Human Cells in Response to Oxidative Stress: Implications in the Pathophysiology and Therapy of Mitochondrial Diseases
Authors: Yu-Ting Wu, Shi-Bei Wu and Yau-Huei WeiMitochondria are the organelles producing most of the energy and play important roles in a variety of biochemical functions in human cells. Mitochondrial defects can cause ATP deficiency and overproduction of reactive oxygen species, which are the major hallmarks of mitochondrial diseases. Abundant evidence has suggested that mitochondrial dysfunction-elicited oxidative stress can play an important role in the pathogenesis and progression of mitochondrial diseases. Mitochondria can respond to energy deficiency by the retrograde signaling to trigger a number of molecular events to help the human cells to cope with physiological or environmental changes. In this article, we first describe oxidative stress-induced cellular responses including metabolic adaptation, compensatory increase of mitochondrial biogenesis, upregulation of antioxidant enzymes, and alteration of protein acetylation in human cells with mitochondrial dysfunction. In this regard, we review recent findings to elucidate the mechanisms by which human cells motivate their mitochondria and the antioxidant defense system to respond to energy deficiency and oxidative stress, which contribute to the adaptive metabolic reprogramming in mitochondrial diseases. In addition, we emphasize the critical role of the activation of AMPK, Sirt1 and Sirt3 in the metabolic adaptation of human cells harboring mitochondrial DNA mutations. Recent studies have revealed that AMPK and sirtuins-mediated signaling pathways are involved in metabolic reprogramming, which is effected by upregulation of antioxidant defense system and mitochondrial protein acetylation, in human cells with mitochondrial dysfunction. Finally, we discuss several potential modulators of bioenergetic function such as coenzyme Q10, mitochondria-targeting antioxidants, resveratrol, and L-carnitine based on recent findings from studies on human cells and animal models of mitochondrial diseases. Elucidation of the signaling pathway of this adaptive response to oxidative stress triggered by mitochondrial dysfunction may enable us to gain a deeper insight into the communication between mitochondria and the nucleus and guide us to develop novel therapeutic agents for effective treatment of mitochondrial diseases.
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Targeting Mitochondrial Biogenesis to Treat Insulin Resistance
Authors: Monica Zamora and Josep A. VillenaOver the last century, the prevalence of type 2 diabetes has dramatically increased, reaching the status of epidemic. Because insulin resistance is considered the primary cause of type 2 diabetes, the identification of the cellular processes and gene networks that lead to an impairment of insulin action in target tissues is of crucial importance for the development of new drugs and therapeutic strategies to treat or prevent the disease. Numerous studies in humans and animal models have shown that insulin resistance is frequently associated to reduced mitochondrial mass or oxidative function in insulin sensitive tissues, leading to the hypothesis that defective overall mitochondrial activity could play a relevant role in the etiology of insulin resistance and, therefore, in type 2 diabetes. Although the causal relationship between mitochondrial dysfunction and insulin resistance is still controversial, numerous studies show that lifestyle or pharmacological interventions that improve insulin sensitivity are frequently associated to an increase in mitochondrial function and whole body energy expenditure. Therefore, increasing mitochondrial mass and oxidative activity is viewed as a potential therapeutic approach for the treatment of insulin resistance. Here, we review the current knowledge on the role of mitochondria in the pathogenesis of insulin resistance and discuss some of the potential therapeutic strategies and pharmacological targets for the treatment of insulin resistance based on the activation of mitochondrial biogenesis and the increase of mitochondrial oxidative function.
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Mitochondria: Prospective Targets for Neuroprotection in Parkinson’s Disease
Authors: Anuradha Yadav, Swati Agarwal, Shashi Kant Tiwari and Rajnish K. ChaturvediParkinson’s disease is the second most common neurodegenerative disorder characterized by persistent loss of dopaminergic neurons in the SN and clinically associated with cognitive, behavioral and motor deficits. There is an enormous amount of data that provides convincing evidence about the prime involvement of mitochondria in the onset and progression of neurodegeneration. Several studies have also emphasized that accumulation of toxic protein and their aggregates in mitochondria lead to energy deficits, excessive ROS generation, mutations in mitochondrial genome and proteins regulating mitochondrial homeostasis, and impaired mitochondrial dynamics in animal models of PD and patients. Here we discuss about the bioenergetic agents, which have been tested for reducing the mitochondrial dysfunction and associated disease pathology in cellular and animal models of PD and PD patients with encouraging outcomes. We also provide a succinct overview of current therapeutic implications of PGC-1α, SIRT, AMPK, and Nrf2-ARE as salutary targets to overcome the deleterious effects posed by mitochondrial dysfunction in the onset and progression of PD.
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Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases
Authors: Martine Uittenbogaard and Anne ChiaramelloIn the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases.
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Phytoestrogens and Mitochondrial Biogenesis in Breast Cancer. Influence of Estrogen Receptors Ratio
Phytoestrogens were originally identified as compounds having a close similarity in structure to estrogens and harboring weak estrogen activity. The interest in phytoestrogens as potential therapeutic agents has recently risen in the field of oncology, since population based studies have linked phytoestrogens consumption with a decreased risk of mortality due to several types of cancer. This review departs from the main focus of these articles by describing recent advances in our understanding of phytoestrogen potential action on mitochondria, specifically on mitochondrial biogenesis, dynamics and functionality, as well as mitoptosis in breast cancer. Further studies are necessary to explain the effects of individual phytoestrogens on mitochondrial biogenesis and dynamics and for designing of new therapy targets for cancer treatment, nevertheless area promising therapeutic approach.
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Mitochondrial Biogenesis in Health and Disease. Molecular and Therapeutic Approaches
Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria. Cells respond to different physiologic, metabolic, and pathologic changes by regulating this organelle with high morphological and functional adaptability. A considerable number of proteins, transcription factors, upstream regulatory proteins and secondary mechanisms are involved in MB and the stabilization of new mitochondrial DNA. These MB activators and regulators, including the main participating proteins (e.g. PGC-1α and mtTFA), are candidates for therapeutic intervention in diverse diseases, like neurodegenerative disorders, metabolic syndrome, sarcopenia, cardiac pathophysiology and physiological processes like aging. In this review, we analyze the implication of MB in several diseases in which the MB pathway is affected. Furthermore, we describe therapeutical interventions on MB targets to boost MB for the prevention and treatment of human diseases. Furthermore, evidence based results and the knowledge gained during last years for some of these drugs aim us hypothesize about the value of a given treatment involved in the activation of MB.
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Regulation and Quantification of Cellular Mitochondrial Morphology and Content
Mitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content (“mitochondrial mass”) depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning (“mitochondrial dynamics”), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.
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Mitochondrial Biogenesis: Regulation By Endogenous Gases During Inflammation and Organ Stress
Authors: Hagir B. Suliman and Claude A. PiantadosiThe influence of mitochondrial dysfunction on pathological states involving inflammatory and/or oxidative stress in tissues that do not show frank cellular apoptosis or necrosis has been rather difficult to unravel, and the literature is replete with contradictory information. Although such discrepancies have many potential causes related to the type of injurious agent, the severity and duration of the injury, and the particular cells and tissues and the functions involved, it is the successful induction of cellular adaptive responses that ultimately governs the resolution of mitochondrial dysfunction and survival of the cell. Much recent attention has been devoted to unraveling the signaling pathways that activate mitochondrial biogenesis and other processes involved in mitochondrial quality control (QC) during inflammatory and oxidative stress with an eye towards the development of novel targets for therapeutic mitigation of the resultant tissue damage. This review provides a brief overview of this emerging field with an emphasis on the role of signaling through the endogenous gases (NO, CO and H2S) and a redox-based approach that brings transparency to key factors that contribute to the resolution of mitochondrial dysfunction and the maintenance of cell vitality. We make the case that targeted stimulation of mitochondrial biogenesis could be a potentially valuable approach for the development of new therapies for the treatment of diseases for which mitochondrial damage is a major consideration.
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Healthspan and Longevity in Mammals: A Family Game for Cellular Organelles?
Authors: Enzo Nisoli and Alessandra ValerioHealthy mitochondria are essential generators of cellular energy, while senescent or damaged mitochondria are bioenergetically inefficient and are sources of reactive oxygen species. The mitochondrial life cycle, comprising biogenesis, fusion/fission events and mitophagic elimination, is carefully orchestrated, and age-related decay of the lifecycle contributes to chronic degenerative diseases. Mitochondria make contacts with other cellular organelles in the endomembrane system (endoplasmic reticulum, peroxisomes and lysosomes) whose dynamics are co-regulated and interactions finely tuned to meet the cell requirements and maintain the health of the organism. This review will consider the evidence that mitochondrial biogenesis and quality control, as well as the complex interplay among cellular organelles, may be affected by the aging process(es), with negative consequences for the well being of elderly individuals. Moreover, we propose that nutrients or drugs able to maintain organelle homeostasis may represent novel preventive and/or therapeutic approaches for chronic age-related diseases.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)