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.

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 Mitochondrial Fusion by M1 Promotes Embryoid Body Cardiac Differentiation of Human Pluripotent Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jarmon G. Lees ◽  
Anne M. Kong ◽  
Yi C. Chen ◽  
Priyadharshini Sivakumaran ◽  
Damián Hernández ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryoid Body ◽  
Mitochondrial Dynamics ◽  
Embryoid Bodies ◽  
Mitochondrial Fusion ◽  
Cardiac Differentiation ◽  
Patient Specific ◽  
Mitochondrial Morphology ◽  
Human Ipscs

Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.

scholarly journals Regulation of mitochondrial fusion by the F-box protein Mdm30 involves proteasome-independent turnover of Fzo1

2006 ◽  
Vol 173 (5) ◽  
pp. 645-650 ◽  
Author(s):  
Mafalda Escobar-Henriques ◽  
Benedikt Westermann ◽  
Thomas Langer
Keyword(s):  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Critical Role ◽  
Mitochondrial Fusion ◽  
Yeast Cells ◽  
Mitochondrial Outer Membrane ◽  
Central Component ◽  
Mitochondrial Morphology ◽  
Proteolytic Pathway ◽  
F Box Protein

Mitochondrial morphology depends on balanced fusion and fission events. A central component of the mitochondrial fusion apparatus is the conserved GTPase Fzo1 in the outer membrane of mitochondria. Mdm30, an F-box protein required for mitochondrial fusion in vegetatively growing cells, affects the cellular Fzo1 concentration in an unknown manner. We demonstrate that mitochondrial fusion requires a tight control of Fzo1 levels, which is ensured by Fzo1 turnover. Mdm30 binds to Fzo1 and, dependent on its F-box, mediates proteolysis of Fzo1. Unexpectedly, degradation occurs along a novel proteolytic pathway not involving ubiquitylation, Skp1–Cdc53–F-box (SCF) E3 ubiquitin ligase complexes, or 26S proteasomes, indicating a novel function of an F-box protein. This contrasts to the ubiquitin- and proteasome-dependent turnover of Fzo1 in α-factor–arrested yeast cells. Our results therefore reveal not only a critical role of Fzo1 degradation for mitochondrial fusion in vegetatively growing cells but also the existence of two distinct proteolytic pathways for the turnover of mitochondrial outer membrane proteins.

scholarly journals Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis

2004 ◽  
Vol 164 (4) ◽  
pp. 493-499 ◽  
Author(s):  
Mariusz Karbowski ◽  
Damien Arnoult ◽  
Hsiuchen Chen ◽  
David C. Chan ◽  
Carolyn L. Smith ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Mitochondrial Dynamics ◽  
Dynamic Balance ◽  
Mitochondrial Fusion ◽  
Confocal Imaging ◽  
Time Range ◽  
Mitochondrial Morphology ◽  
Green Fluorescent ◽  
Mitochondrial Membrane Permeabilization ◽  
Activation Phase

A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix–targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis.

scholarly journals Molecular Machinery and Pathophysiology of Mitochondrial Dynamics

2021 ◽  
Vol 9 ◽  
Author(s):  
Yi-Han Chiu ◽  
Shu-Chuan Amy Lin ◽  
Chen-Hsin Kuo ◽  
Chia-Jung Li
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Biological Significance ◽  
Lipid Synthesis ◽  
Mitochondrial Morphology ◽  
Animal Cells ◽  
Main Site ◽  
Mechanical Proteins ◽  
Molecular Machinery ◽  
Active Processes

Mitochondria are double-membraned organelles that exhibit fluidity. They are the main site of cellular aerobic respiration, providing energy for cell proliferation, migration, and survival; hence, they are called “powerhouses.” Mitochondria play an important role in biological processes such as cell death, cell senescence, autophagy, lipid synthesis, calcium homeostasis, and iron balance. Fission and fusion are active processes that require many specialized proteins, including mechanical enzymes that physically alter mitochondrial membranes, and interface proteins that regulate the interaction of these mechanical proteins with organelles. This review discusses the molecular mechanisms of mitochondrial fusion, fission, and physiopathology, emphasizing the biological significance of mitochondrial morphology and dynamics. In particular, the regulatory mechanisms of mitochondria-related genes and proteins in animal cells are discussed, as well as research trends in mitochondrial dynamics, providing a theoretical reference for future mitochondrial research.

scholarly journals Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

2019 ◽  
Author(s):  
Yanjun Kou ◽  
Yunlong He ◽  
Jiehua Qiu ◽  
Shu Yazhou ◽  
Fan Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Blast Disease ◽  
Cereal Crops ◽  
Mitochondrial Morphology ◽  
Invasive Growth ◽  
In Planta ◽  
Antioxidant Treatment

SUMMARYMagnaporthe oryzaecauses Blast disease, which is one of the most devastating infections in rice and several important cereal crops.M. oryzaeneeds to coordinate gene regulation, morphological changes, nutrient acquisition, and host evasion, in order to invade and proliferate within the plant tissues. Thus far, the molecular mechanisms underlying the regulation of invasive growthin plantahave remained largely unknown. We identified a precise filamentous-punctate-filamentous cycle in mitochondrial morphology duringMagnaporthe-Rice interaction. Interestingly, loss of either the mitochondrial fusion (MoFzo1) or fission (MoDnm1) machinery, or inhibition of mitochondrial fission using Mdivi-1 caused significant reduction inM. oryzaepathogenicity. Furthermore, exogenous carbon source(s) but not antioxidant treatment delayed such mitochondrial dynamics/transition during invasive growth. Such nutrient-based regulation of organellar dynamics preceded MoAtg24-mediated mitophagy, which was found to be essential for proper biotrophic development and invasive growthin planta. We propose that precise mitochondrial dynamics and mitophagy occur during the transition from biotrophy to necrotrophy, and are required for proper induction and establishment of the blast disease in rice.

scholarly journals Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila

2021 ◽  
Author(s):  
Dnyanesh Dubal ◽  
Prachiti Moghe ◽  
Bhavin Uttekar ◽  
Richa Rikhy
Keyword(s):  
Notch Signaling ◽  
Mitochondrial Dynamics ◽  
Stem Cell Differentiation ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Type Ii ◽  
Mitochondrial Fragmentation ◽  
Proliferation And Differentiation

Optimal mitochondrial function determined by mitochondrial dynamics, morphology and activity is coupled to stem cell differentiation and organism development. However, the mechanisms of interaction of signaling pathways with mitochondrial morphology and activity are not completely understood. We assessed the role of mitochondrial fusion and fission in differentiation of neural stem cells called neuroblasts (NB) in the Drosophila brain. Depletion of mitochondrial inner membrane fusion protein Opa1 and mitochondrial outer membrane protein Marf in the Drosophila type II neuroblast lineage led to mitochondrial fragmentation and loss of activity. Opa1 and Marf depletion did not affect the numbers and polarity of type II neuroblasts but led to a decrease in proliferation and differentiation of cells in the lineage. On the contrary, loss of mitochondrial fission protein Drp1 led to mitochondrial fusion but did not show defects in proliferation and differentiation. Depletion of Drp1 along with Opa1 or Marf also led to mitochondrial fusion and suppressed fragmentation, loss of mitochondrial activity, proliferation and differentiation in the type II NB lineage. We found that Notch signaling depletion via the canonical pathway showed mitochondrial fragmentation and loss of differentiation similar to Opa1 mutants. An increase in Notch signaling required mitochondrial fusion for NB proliferation. Further, Drp1 mutants in combination with Notch depletion showed mitochondrial fusion and drove differentiation in the lineage suggesting that fused mitochondria can influence Notch signaling driven differentiation in the type II NB lineage. Our results implicate a crosstalk between Notch signalling, mitochondrial activity and mitochondrial fusion as an essential step in type II NB differentiation.

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling

2019 ◽  
Vol 115 (13) ◽  
pp. 1873-1885 ◽  
Author(s):  
Genki Naruse ◽  
Hiromitsu Kanamori ◽  
Akihiro Yoshida ◽  
Shingo Minatoguchi ◽  
Tomonori Kawaguchi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Mitochondrial Dynamics ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Atp Content ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

Abstract Aims Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production. Methods and results Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out. Conclusions Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Abstract 393: MCL-1 Promotes Survival and Influences Mitochondrial Dynamics in Cardiac Myocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra G Moyzis ◽  
Robert L Thomas ◽  
Jennifer Kuo ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Rapid Degradation

The BCL-2 family proteins are important regulators of mitochondrial structure and integrity. MCL-1 is an anti-apoptotic BCL-2 protein that is highly expressed in the myocardium compared to the other anti-apoptotic proteins BCL-2 and BCL-X L. Recently, we reported that MCL-1 is essential for myocardial homeostasis. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 deficient myocytes did not undergo apoptotic cell death. Instead, the cells displayed signs of mitochondrial deterioration and necrotic cell death, suggesting that MCL-1 has an additional role in maintaining mitochondrial function in cardiac myocytes. Similarly, deletion of MCL-1 in fibroblasts caused rapid mitochondrial fragmentation followed by cell death at 72 hours. Interestingly, the MCL-1 deficient fibroblasts retained cytochrome c in the mitochondria , confirming that the cells were not undergoing apoptotic cell death. We have also identified that MCL-1 localizes to the mitochondrial outer membrane (OM) and the matrix in the myocardium and that the two forms respond differently to stress. MCL-1 OM was rapidly degraded after myocardial infarction or fasting, whereas MCL-1 Matrix levels were maintained. Similarly, starvation of MEFs resulted in rapid degradation of MCL-1 OM , whereas MCL-1 Matrix showed delayed degradation. Treatment with the mitochondrial uncoupler FCCP led to rapid degradation of both forms. This suggests that the susceptibility to degradation is dependent on its localization and the nature of the stress. Our data also suggests that these two forms perform distinct functions in regulating mitochondrial morphology and survival. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission and clearance by autophagosomes. Thus, our data suggest that MCL-1 exists in two separate locations where it performs different functions. MCL-1 Matrix promotes mitochondrial fusion, which protects cells against excessive mitochondrial clearance during unfavorable conditions.

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.

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