scholarly journals Mitochondrial Fusion Proteins and Human Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Michela Ranieri ◽  
Simona Brajkovic ◽  
Giulietta Riboldi ◽  
Dario Ronchi ◽  
Federica Rizzo ◽  
...  
Keyword(s):  
Optic Atrophy ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Human Diseases ◽  
Dna Amount ◽  
Charcot Marie Tooth Disease ◽  
Parkinson’S Diseases ◽  
Genes Encoding ◽  
Cell Alterations

Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

scholarly journals When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Disease Development ◽  
Pathological Conditions ◽  
Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

scholarly journals Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Paula Juárez ◽  
Francesc Palau
Keyword(s):  
Schwann Cell ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Sensory Nerves ◽  
Peripheral Neuropathies ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Molecular Features ◽  
Tooth Disease

In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.

scholarly journals Nonredundant Roles of Mitochondria-associated F-Box Proteins Mfb1 and Mdm30 in Maintenance of Mitochondrial Morphology in Yeast

2006 ◽  
Vol 17 (9) ◽  
pp. 3745-3755 ◽  
Author(s):  
Mark Dürr ◽  
Mafalda Escobar-Henriques ◽  
Sandra Merz ◽  
Stefan Geimer ◽  
Thomas Langer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Mitochondrial Inheritance ◽  
Physiological Conditions ◽  
Cellular Processes ◽  
Protein Mutants ◽  
Homozygous Diploid ◽  
F Box Protein

Mitochondria constantly fuse and divide to adapt organellar morphology to the cell’s ever-changing physiological conditions. Little is known about the molecular mechanisms regulating mitochondrial dynamics. F-box proteins are subunits of both Skp1-Cullin-F-box (SCF) ubiquitin ligases and non-SCF complexes that regulate a large number of cellular processes. Here, we analyzed the roles of two yeast F-box proteins, Mfb1 and Mdm30, in mitochondrial dynamics. Mfb1 is a novel mitochondria-associated F-box protein. Mitochondria in mutants lacking Mfb1 are fusion competent, but they form aberrant aggregates of interconnected tubules. In contrast, mitochondria in mutants lacking Mdm30 are highly fragmented due to a defect in mitochondrial fusion. Fragmented mitochondria are docked but nonfused in Δmdm30 cells. Mitochondrial fusion is also blocked during sporulation of homozygous diploid mutants lacking Mdm30, leading to a mitochondrial inheritance defect in ascospores. Mfb1 and Mdm30 exert nonredundant functions and likely have different target proteins. Because defects in F-box protein mutants could not be mimicked by depletion of SCF complex and proteasome core subunits, additional yet unknown factors are likely involved in regulating mitochondrial dynamics. We propose that mitochondria-associated F-box proteins Mfb1 and Mdm30 are key components of a complex machinery that regulates mitochondrial dynamics throughout yeast’s entire life cycle.

Membranes in motion: mitochondrial dynamics and their role in apoptosis

2014 ◽  
Vol 395 (3) ◽  
pp. 297-311 ◽  
Author(s):  
Begoña Ugarte-Uribe ◽  
Ana J. García-Sáez
Keyword(s):  
Cell Survival ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Neurologic Disorders

Abstract Mitochondrial dynamics is crucial for cell survival, development and homeostasis and impairment of these functions leads to neurologic disorders and metabolic diseases. The key components of mitochondrial dynamics have been identified. Mitofusins and OPA1 mediate mitochondrial fusion, whereas Drp1 is responsible for mitochondrial fission. In addition, an interplay between the proteins of the mitochondrial fission/fusion machinery and the Bcl-2 proteins, essential mediators in apoptosis, has been also described. Here, we review the molecular mechanisms regarding mitochondrial dynamics together with their role in apoptosis.

scholarly journals Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3436
Author(s):  
Leonie M. Heger ◽  
Rachel M. Wise ◽  
Jara Tabitha Hees ◽  
Angelika B. Harbauer ◽  
Lena F. Burbulla
Keyword(s):  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Cellular Systems ◽  
Calcium Handling ◽  
Patient Specific ◽  
Central Feature ◽  
Parkinson’S Diseases

Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson’s disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients’ somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.

Molecular Mechanisms of Curcumin in Neuroinflammatory Disorders: A Mini Review of Current Evidences

2019 ◽  
Vol 19 (3) ◽  
pp. 247-258 ◽  
Author(s):  
Mahsa Hatami ◽  
Mina Abdolahi ◽  
Neda Soveyd ◽  
Mahmoud Djalali ◽  
Mansoureh Togha ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
English Language ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Mitochondrial Dynamics ◽  
Nuclear Factor Κb ◽  
General Term ◽  
Neuroinflammatory Disease ◽  
Tnf Α ◽  
Factor Α

Objective: Neuroinflammatory disease is a general term used to denote the progressive loss of neuronal function or structure. Many neuroinflammatory diseases, including Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), occur due to neuroinflammation. Neuroinflammation increases nuclear factor-κB (NF-κB) levels, cyclooxygenase-2 enzymes and inducible nitric oxide synthase, resulting in the release of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It could also lead to cellular deterioration and symptoms of neuroinflammatory diseases. Recent studies have suggested that curcumin (the active ingredient in turmeric) could alleviate the process of neuroinflammatory disease. Thus, the present mini-review was conducted to summarize studies regarding cellular and molecular targets of curcumin relevant to neuroinflammatory disorders. Methods: A literature search strategy was conducted for all English-language literature. Studies that assessed the various properties of curcuminoids in respect of neuroinflammatory disorders were included in this review. Results: The studies have suggested that curcuminoids have significant anti- neuroinflammatory, antioxidant and neuroprotective properties that could attenuate the development and symptom of neuroinflammatory disorders. Curcumin can alleviate neurodegeneration and neuroinflammation through multiple mechanisms, by reducing inflammatory mediators (such as TNF-α, IL-1β, nitric oxide and NF-κB gene expression), and affect mitochondrial dynamics and even epigenetic changes. Conclusion: It is a promising subject of study in the prevention and management of the neuroinflammatory disease. However, controlled, randomized clinical trials are needed to fully evaluate its clinical potential.

scholarly journals Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianli He ◽  
Xun Shangguan ◽  
Wei Zhou ◽  
Ying Cao ◽  
Quan Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Metabolic Reprogramming ◽  
Negative Regulator ◽  
T Cell Memory ◽  
Memory Development ◽  
Cell Memory ◽  
Glucose Limitation ◽  
Glycolytic Intermediate

AbstractMetabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.

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