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Antonio Zorzano - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Dynamics: A Journey from Mitochondrial Morphology to Mitochondrial Function and Quality
Mitochondrial Biology and Experimental Therapeutics, 2018Co-Authors: David Sebastián, Antonio ZorzanoAbstract:Mitochondria were considered in the past as static and isolated organelles inside the cell. However, currently it is clear that they change in shape, and they are continuously moving along the cell forming an interconnected and highly dynamic network. The sum of all these processes are referred to as Mitochondrial Dynamics. In addition to the control of Mitochondrial morphology and movement, a large number of evidences have turned Mitochondrial Dynamics into a key factor controlling Mitochondrial function and quality, having an important role in respiration, oxidative metabolism, Ca2+ homeostasis, Mitochondrial quality control, autophagy and apoptosis. The importance of Mitochondrial Dynamics in physiology is reflected by the increasing number of pathologies associated with its dysregulation, such as neuropathies, neurodegenerative diseases, atherosclerosis, metabolic diseases, sarcopenia and aging. Therefore, the factors regulating Mitochondrial Dynamics and the understanding of the molecular mechanisms by which Mitochondrial Dynamics regulates key aspects of Mitochondrial biology is of great importance. In this chapter, we will focus on the proteins involved in Mitochondrial Dynamics, their regulation and their impact in the control of Mitochondrial function and quality.
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Mitochondrial Dynamics and metabolic homeostasis
Current Opinion in Physiology, 2018Co-Authors: David Sebastián, Antonio ZorzanoAbstract:Mitochondria display key cellular functions, such as respiration, oxidative metabolism, calcium homeostasis, lipid metabolism, antiviral signaling, senescence and apoptosis. Therefore, the control of Mitochondrial biology is a crucial aspect for cellular homeostasis. In the last years, a substantial amount of evidence have turned Mitochondrial Dynamics into a key aspect of Mitochondrial biology, not only by controlling Mitochondrial metabolism, but also by preserving Mitochondrial quality. Dysregulation of Mitochondrial Dynamics is found in a variety of pathologies. Moreover, alterations in Mitochondrial Dynamics proteins lead to Mitochondrial abnormalities, characterized by accumulation of damaged and dysfunctional mitochondria, which are involved in neurodegenerative diseases, muscle atrophy, sarcopenia, aging and metabolic diseases such as type 2 diabetes or obesity. In this review, we will focus on how Mitochondrial Dynamics, by controlling Mitochondrial function and quality, has emerged as a regulator of metabolic homeostasis, and how its dysregulation is involved in the development of metabolic diseases.
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Mitochondrial Dynamics: Coupling Mitochondrial Fitness with Healthy Aging
Trends in Molecular Medicine, 2017Co-Authors: David Sebastián, Manuel Palacín, Antonio ZorzanoAbstract:Aging is associated with a decline in Mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these Mitochondrial alterations and the role of the latter in aging are still not fully understood. Mitochondrial Dynamics is a key process regulating Mitochondrial function and quality. Altered expression of some Mitochondrial Dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans, mice, and humans. Here, we review the link between alterations in Mitochondrial Dynamics, aging, and age-related impairment. We propose that the dysregulation of Mitochondrial Dynamics leads to age-induced accumulation of unhealthy mitochondria and contributes to alterations linked to aging, such as diabetes and neurodegeneration.
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Implications of Mitochondrial Dynamics on neurodegeneration and on hypothalamic dysfunction
Frontiers in Aging Neuroscience, 2015Co-Authors: Antonio Zorzano, Marc ClaretAbstract:Mitochondrial Dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of Mitochondrial fusion and fission. Mutations in two Mitochondrial fusion genes (MFN2 and OPA1) cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy (ADOA). Alterations in Mitochondrial Dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of Mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of Mitochondrial Dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.
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Mitochondrial Dynamics in Mammalian Health and Disease
Physiological Reviews, 2009Co-Authors: Marc Liesa, Manuel Palacín, Antonio ZorzanoAbstract:The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of Mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial Dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of Mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in Mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for Mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two Mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established Mitochondrial Dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of Mitochondrial Dynamics in mammalian cells and their implication in human pathologies.
Orian S. Shirihai - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Dynamics in the regulation of nutrient utilization and energy expenditure
Cell Metabolism, 2013Co-Authors: Marc Liesa, Orian S. ShirihaiAbstract:Mitochondrial fusion, fission, and mitophagy form an essential axis of Mitochondrial quality control. However, quality control might not be the only task carried out by Mitochondrial Dynamics. Recent studies link Mitochondrial Dynamics to the balance between energy demand and nutrient supply, suggesting changes in Mitochondrial architecture as a mechanism for bioenergetic adaptation to metabolic demands. By favoring either connected or fragmented architectures, Mitochondrial Dynamics regulates bioenergetic efficiency and energy expenditure. Placement of bioenergetic adaptation and quality control as competing tasks of Mitochondrial Dynamics might provide a new mechanism, linking excess nutrient environment to progressive Mitochondrial dysfunction, common to age-related diseases.
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Mitochondrial Dynamics: The Intersection of Form and Function
Advances in Experimental Medicine and Biology, 2012Co-Authors: Andrew Ferree, Orian S. ShirihaiAbstract:Mitochondria within a cell exist as a population in a dynamic morphological continuum. The balance of Mitochondrial fusion and fission dictates a spectrum of shapes from interconnected networks to fragmented individual units. This plasticity bestows the adaptive flexibility needed to adjust to changing cellular stresses and metabolic demands. The mechanisms that regulate Mitochondrial Dynamics, their importance in normal cell biology, and the roles they play in disease conditions are only beginning to be understood. Dysfunction of Mitochondrial Dynamics has been identified as a possible disease mechanism in Parkinson’s disease. This chapter will introduce the budding field of Mitochondrial Dynamics and explore unique characteristics of affected neurons in Parkinson’s disease that increase susceptibility to disruptions in Mitochondrial Dynamics.
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The Interplay Between Mitochondrial Dynamics and Mitophagy
Antioxidants & Redox Signaling, 2011Co-Authors: Gilad Twig, Orian S. ShirihaiAbstract:Abstract Mitochondrial Dynamics and mitophagy are recognized as two critical processes underlying Mitochondrial homeostasis. Morphological and bioenergetic characterization of the life cycle of an individual mitochondrion reveals several points where fusion, fission, and mitophagy interact. Mitochondrial fission can produce an impaired daughter unit that will be targeted by the autophagic machinery. Mitochondrial fusion, on the other hand, may serve to dilute impaired respiratory components and thereby prevent their removal. The inverse dependency of fusion and mitophagy on membrane potential allows them to act as complementary rather than competitive fates of the daughter mitochondrion after a fission event. We discuss the interplay between Mitochondrial Dynamics and mitophagy in different tissues and in different disease models under both stress-induced and steady-state conditions. Antioxid. Redox Signal. 14, 1939–1951.
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Mitochondrial Dynamics and Autophagy
Mitochondrial Dynamics and Neurodegeneration, 2011Co-Authors: Linsey Stiles, Andrew Ferree, Orian S. ShirihaiAbstract:Efficient Mitochondrial quality control is critical for maintenance of a healthy Mitochondrial population. Both Mitochondrial Dynamics and selective Mitochondrial autophagy, termed mitophagy, contribute to Mitochondrial turnover and quality control. Mitochondrial fusion and fission allow for complementation of Mitochondrial solutes, proteins, and DNA but also for generation of unequal daughter organelles. Selective fusion is utilized for incorporation of polarized mitochondria back into the network, while a depolarized mitochondrion will not fuse, but instead will be targeted for elimination by mitophagy. Mitophagy is dependent on Mitochondrial dysfunction, such as depolarization, and a number of proteins are required for core autophagic machinery, signaling, and Mitochondrial segregation and targeting. The relationship between Mitochondrial Dynamics and autophagy and how they may contribute to both Mitochondrial and cellular quality control is beginning to be elucidated. Even with the questions that remain in regards to the regulation and interdependence of Mitochondrial Dynamics and mitophagy, it is clear that alterations in these processes lead to Mitochondrial dysfunction and pathological states such as neurodegeneration.
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Mitochondrial Dynamics and metabolic regulation
The FASEB Journal, 2011Co-Authors: Orian S. Shirihai, David C. Chan, Linsey Stiles, Anthony J.a. Molina, Guy Las, Sam Sereda, György Hajnóczky, Barbara E. CorkeyAbstract:Mitochondria are dynamic organelles that frequently undergo fusion and fission. Mitochondrial Dynamics has been shown to be essential for a variety of cellular functions. We have previously shown t...
Xinglong Wang - One of the best experts on this subject based on the ideXlab platform.
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Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases
Antioxidants, 2017Co-Authors: Ju Gao, Luwen Wang, Jingyi Liu, Fei Xie, Xinglong WangAbstract:Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are involved in a number of neuronal functions. Mitochondrial dysfunction has long been demonstrated as a common prominent early pathological feature of a variety of common neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Mitochondria are highly dynamic organelles that undergo continuous fusion, fission, and transport, the processes of which not only control Mitochondrial morphology and number but also regulate Mitochondrial function and location. The importance of Mitochondrial Dynamics in the pathogenesis of neurodegenerative diseases has been increasingly unraveled after the identification of several key fusion and fission regulators such as Drp1, OPA1, and mitofusins. In this review, after a brief discussion of molecular mechanisms regulating Mitochondrial fusion, fission, distribution, and trafficking, as well as the important role of Mitochondrial Dynamics for neuronal function, we review previous and the most recent studies about Mitochondrial dynamic abnormalities observed in various major neurodegenerative diseases and discuss the possibility of targeting Mitochondrial Dynamics as a likely novel therapeutic strategy for neurodegenerative diseases.
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the als disease associated mutant tdp 43 impairs Mitochondrial Dynamics and function in motor neurons
Human Molecular Genetics, 2013Co-Authors: Wenzhang Wang, Wen Lang Lin, Dennis W Dickson, Leonard Petrucelli, Teng Zhang, Xinglong WangAbstract:Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired Mitochondrial Dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact Mitochondrial Dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced Mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased Mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating Mitochondrial Dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired Mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal Mitochondrial Dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of Mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced Mitochondrial Dynamics abnormalities and Mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs Mitochondrial Dynamics through enhanced localization on mitochondria, which causes Mitochondrial dysfunction. Therefore, abnormal Mitochondrial Dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.
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Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer's Disease?
Molecular Neurobiology, 2010Co-Authors: Bo Su, Xinglong Wang, David Bonda, Gorge Perry, Mark SmithAbstract:Mitochondria are dynamic organelles that undergo continuous fission and fusion, which could affect all aspects of Mitochondrial function. Mitochondrial dysfunction has been well documented in Alzheimer’s disease (AD). In the past few years, emerging evidence indicates that an imbalance of Mitochondrial Dynamics is involved in the pathogenesis of AD. In this review, we discuss in detail the abnormal Mitochondrial Dynamics in AD and how such abnormal Dynamics may impact Mitochondrial and neuronal function and contribute to the course of disease. Based on this discussion, we propose that Mitochondrial Dynamics could be a potential therapeutic target for AD.
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Abnormal Mitochondrial Dynamics--a novel therapeutic target for Alzheimer's disease?
Molecular Neurobiology, 2010Co-Authors: Xinglong Wang, David Bonda, Gorge Perry, Mark Smith, Xiongwei ZhuAbstract:Mitochondria are dynamic organelles that undergo continuous fission and fusion, which could affect all aspects of Mitochondrial function. Mitochondrial dysfunction has been well documented in Alzheimer's disease (AD). In the past few years, emerging evidence indicates that an imbalance of Mitochondrial Dynamics is involved in the pathogenesis of AD. In this review, we discuss in detail the abnormal Mitochondrial Dynamics in AD and how such abnormal Dynamics may impact Mitochondrial and neuronal function and contribute to the course of disease. Based on this discussion, we propose that Mitochondrial Dynamics could be a potential therapeutic target for AD.
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Abnormal Mitochondrial Dynamics and neurodegenerative diseases.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010Co-Authors: Xinglong Wang, Ling Zheng, George Perry, Mark A. Smith, Xiongwei ZhuAbstract:Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases. A deeper understanding of the remarkably dynamic nature of mitochondria, characterized by a delicate balance of fission and fusion, has helped to fertilize a recent wave of new studies demonstrating abnormal Mitochondrial Dynamics in neurodegenerative diseases. This review highlights Mitochondrial dysfunction and abnormal Mitochondrial Dynamics in Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease and discusses how these abnormal Mitochondrial Dynamics may contribute to Mitochondrial and neuronal dysfunction. We propose that abnormal Mitochondrial Dynamics represents a key common pathway that mediates or amplifies Mitochondrial dysfunction and neuronal dysfunction during the course of neurodegeneration.
Pascale Cossart - One of the best experts on this subject based on the ideXlab platform.
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Listeria infection modulates Mitochondrial Dynamics
Communicative & Integrative Biology, 2011Co-Authors: Fabrizia Stavru, Pascale CossartAbstract:Mitochondria are highly dynamic organelles that are central to several cellular processes, the most prominent being energy production. Several reports have shown that pathogens target mitochondria in various ways to interfere with apoptosis, but to our knowledge only one study has specifically addressed the effects of infection on Mitochondrial Dynamics. We focused on this aspect during infection with the intracellular pathogen L. monocytogenes and could recently show that this bacterium profoundly alters Mitochondrial Dynamics, causing transient fragmentation of the Mitochondrial network. This Mitochondrial fragmentation occurs early during infection and is specific to pathogenic L. monocytogenes, as it is not observed with other intracellular pathogens. The relevance of Mitochondrial Dynamics for L. monocytogenes infection is highlighted by the finding that siRNA-mediated inhibition of Mitochondrial fusion or fission decreases or increases the efficiency of L. monocytogenes infection, respectively. The main bacterial factor responsible for Mitochondrial network disruption was identified as the secreted pore-forming toxin listeriolysin O, which also appeared to impair Mitochondrial function. Our work suggests that in order to establish an efficient infection, L. monocytogenes interferes with cellular physiology at early timepoints by transient disruption of Mitochondrial Dynamics and function.
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Listeria monocytogenes transiently alters Mitochondrial Dynamics during infection
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Fabrizia Stavru, Frédéric Bouillaud, Anna Sartori, Daniel Ricquier, Pascale CossartAbstract:Mitochondria are essential and highly dynamic organelles, constantly undergoing fusion and fission. We analyzed Mitochondrial Dynamics during infection with the human bacterial pathogen Listeria monocytogenes and show that this infection profoundly alters Mitochondrial Dynamics by causing transient Mitochondrial network fragmentation. Mitochondrial fragmentation is specific to pathogenic Listeria monocytogenes, and it is not observed with the nonpathogenic Listeria innocua species or several other intracellular pathogens. Strikingly, the efficiency of Listeria infection is affected in cells where either Mitochondrial fusion or fission has been altered by siRNA treatment, highlighting the relevance of Mitochondrial Dynamics for Listeria infection. We identified the secreted pore-forming toxin listeriolysin O as the bacterial factor mainly responsible for Mitochondrial network disruption and Mitochondrial function modulation. Together, our results suggest that the transient shutdown of Mitochondrial function and Dynamics represents a strategy used by Listeria at the onset of infection to interfere with cellular physiology.
Sarah B. Berman - One of the best experts on this subject based on the ideXlab platform.
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The interplay of neuronal Mitochondrial Dynamics and bioenergetics: Implications for Parkinson's disease
Neurobiology of Disease, 2013Co-Authors: Victor S. Van Laar, Sarah B. BermanAbstract:The dynamic properties of mitochondria (Mitochondrial fission, fusion, transport biogenesis and degradation) are critical for neuronal function and health, and dysregulation of Mitochondrial Dynamics has been increasingly linked to the pathogenesis of Parkinson's disease (PD). Mitochondrial Dynamics and bioenergetics are interconnected, and this is of particular importance in neurons, which have a unique bioenergetic profile due to their energetic dependence on mitochondria and specialized, compartmentalized energetic needs. In this review, we summarize the interplay of Mitochondrial Dynamics and bioenergetics, and its particular relevance for neurodegeneration. Evidence linking dysregulation of Mitochondrial Dynamics to PD is presented from both toxin and genetic models, including newly emerging details of how PD-relevant genes PTEN-induced kinase 1 (PINK1) and Parkin regulate fission, fusion, mitophagy and transport. Finally, we discuss how neuronal bioenergetics may impact PD-relevant regulation of Mitochondrial Dynamics, and possible implications for understanding the role of Mitochondrial Dynamics in PD.
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Mitochondrial Dynamics in Parkinson's disease.
Experimental Neurology, 2009Co-Authors: Victor S. Van Laar, Sarah B. BermanAbstract:The unique energy demands of neurons require well-orchestrated distribution and maintenance of mitochondria. Thus, dynamic properties of mitochondria, including fission, fusion, trafficking, biogenesis, and degradation, are critical to all cells, but may be particularly important in neurons. Dysfunction in Mitochondrial Dynamics has been linked to neuropathies and is increasingly being linked to several neurodegenerative diseases, but the evidence is particularly strong, and continuously accumulating, in Parkinson's disease (PD). The unique characteristics of neurons that degenerate in PD may predispose those neuronal populations to susceptibility to alterations in Mitochondrial Dynamics. In addition, evidence from PD-related toxins supports that Mitochondrial fission, fusion, and transport may be involved in pathogenesis. Furthermore, rapidly increasing evidence suggests that two proteins linked to familial forms of the disease, parkin and PINK1, interact in a common pathway to regulate Mitochondrial fission/fusion. Parkin may also play a role in maintaining Mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Taken together, the current data suggests that Mitochondrial Dynamics may play a role in PD pathogenesis, and a better understanding of Mitochondrial Dynamics within the neuron may lead to future therapeutic treatments for PD, potentially aimed at some of the earliest pathogenic events.