Foriel S, Renkema GH, Lasarzewski Y, Berkhout J, Rodenburg RJ, Smeitink JAM, Beyrath J, Schenck A. A Drosophila Mitochondrial Complex I Deficiency Phenotype Array. Front Genet. 2019 Mar 27;10:245. PMID: 30972103; PMCID: PMC6445954.
Abstract: "Mitochondrial diseases are a group of rare life-threatening diseases often caused by defects in the oxidative phosphorylation system. No effective treatment is available for these disorders. Therapeutic development is hampered by the high heterogeneity in genetic, biochemical, and clinical spectra of mitochondrial diseases and by limited preclinical resources to screen and identify effective treatment candidates. Alternative models of the pathology are essential to better understand mitochondrial diseases and to accelerate the development of new therapeutics. The fruit fly Drosophila melanogaster is a cost- and time-efficient model that can recapitulate a wide range of phenotypes observed in patients suffering from mitochondrial disorders. We targeted three important subunits of complex I of the mitochondrial oxidative phosphorylation system with the flexible UAS-Gal4 system and RNA interference (RNAi): NDUFS4 (ND-18), NDUFS7 (ND-20), and NDUFV1 (ND-51). Using two ubiquitous driver lines at two temperatures, we established a collection of phenotypes relevant to complex I deficiencies. Our data offer models and phenotypes with different levels of severity that can be used for future therapeutic screenings. These include qualitative phenotypes that are amenable to high-throughput drug screening and quantitative phenotypes that require more resources but are likely to have increased potential and sensitivity to show modulation by drug treatment."
Showing posts with label Mitochondrial-related disorders. Show all posts
Showing posts with label Mitochondrial-related disorders. Show all posts
Monday, April 22, 2019
Saturday, April 20, 2019
Rapamycin and succinate dehydrogenase deficiency
Fan F, Sam R, Ryan E, Alvarado K, Villa-Cuesta E. Rapamycin as a potential treatment for succinate dehydrogenase deficiency. Heliyon. 2019 Feb 11;5(2):e01217. PMID: 30805566; PMCID: PMC6374580.
Abstract: "Drosophila melanogaster is a powerful model to study mitochondrial respiratory chain defects, particularly succinate dehydrogenase (SDH) deficiency. Mutations in sdh genes cause degenerative disorders and often lead to death. Therapies for such pathologies are based on a combination of vitamins and dietary supplements, and are rarely effective. In Drosophila, mutations in several of the genes encoding SDH resemble the pathology of SDH deficiency in humans, enabling the Drosophila model to be used in finding treatments for this condition. Here we show that exposure to the drug rapamycin improves the survival of sdh mutant strains, the activity of SDH and the impaired climbing associated with sdh mutations. However, the production of reactive oxygen species, the oxygen consumption of isolated mitochondria and the resistance to hyperoxia were minimally affected. Our results contribute to the current research seeking a treatment for mitochondrial disease."
Abstract: "Drosophila melanogaster is a powerful model to study mitochondrial respiratory chain defects, particularly succinate dehydrogenase (SDH) deficiency. Mutations in sdh genes cause degenerative disorders and often lead to death. Therapies for such pathologies are based on a combination of vitamins and dietary supplements, and are rarely effective. In Drosophila, mutations in several of the genes encoding SDH resemble the pathology of SDH deficiency in humans, enabling the Drosophila model to be used in finding treatments for this condition. Here we show that exposure to the drug rapamycin improves the survival of sdh mutant strains, the activity of SDH and the impaired climbing associated with sdh mutations. However, the production of reactive oxygen species, the oxygen consumption of isolated mitochondria and the resistance to hyperoxia were minimally affected. Our results contribute to the current research seeking a treatment for mitochondrial disease."
Sleep defects observed in fly model of mitochondrial encephalomyopathies
Fogle KJ, Mobini CL, Paseos AS, Palladino MJ. Sleep and circadian defects in a Drosophila model of mitochondrial encephalomyopathy. Neurobiol Sleep Circadian Rhythms. 2019 Jan;6:44-52. PMID: 30868108; PMCID: PMC6411073.
From the abstract: "Mitochondrial encephalomyopathies (ME) are complex, incurable diseases characterized by severe bioenergetic distress that can affect the function of all major organ systems but is especially taxing to neuromuscular tissues. Animal models of MEs are rare, but the Drosophila ATP61 mutant ... accurately models progressive human mitochondrial diseases such as Maternally-Inherited Leigh Syndrome (MILS), Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP), and Familial Bilateral Striatal Necrosis (FBSN). While it is established that this model exhibits important hallmarks of ME ... it is unknown whether it exhibits defects in sleep or circadian function. This is a clinically relevant question, as many neurological and neurodegenerative diseases are characterized by such disturbances, which can exacerbate other symptoms and worsen quality of life. ... we found that day-time and night-time activity and sleep are altered through disease progression, and that circadian patterns are disrupted at both the behavioral and neuronal levels. These results establish ATP61 as an important model of sleep and circadian disruption in ME that can be studied mechanistically at the molecular, cellular, and behavioral level to uncover underlying pathophysiology and test novel therapies."
From the abstract: "Mitochondrial encephalomyopathies (ME) are complex, incurable diseases characterized by severe bioenergetic distress that can affect the function of all major organ systems but is especially taxing to neuromuscular tissues. Animal models of MEs are rare, but the Drosophila ATP61 mutant ... accurately models progressive human mitochondrial diseases such as Maternally-Inherited Leigh Syndrome (MILS), Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP), and Familial Bilateral Striatal Necrosis (FBSN). While it is established that this model exhibits important hallmarks of ME ... it is unknown whether it exhibits defects in sleep or circadian function. This is a clinically relevant question, as many neurological and neurodegenerative diseases are characterized by such disturbances, which can exacerbate other symptoms and worsen quality of life. ... we found that day-time and night-time activity and sleep are altered through disease progression, and that circadian patterns are disrupted at both the behavioral and neuronal levels. These results establish ATP61 as an important model of sleep and circadian disruption in ME that can be studied mechanistically at the molecular, cellular, and behavioral level to uncover underlying pathophysiology and test novel therapies."
Wednesday, April 10, 2019
Fly and yeast models help identify genetic variants of WARS2 as disease-causing for a mitochondrial-related leukoencephalopathy
Maffezzini C, Laine I, Dallabona C, Clemente P, Calvo-Garrido J, Wibom R, Naess K, Barbaro M, Falk A, Donnini C, Freyer C, Wredenberg A, Wedell A. Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy. Mol Genet Genomic Med. 2019 Mar 28:e654. PMID: 30920170.
From the abstract: "Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts. ... Whole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity. ... Biochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality. ... Our results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system."
From the abstract: "Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts. ... Whole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity. ... Biochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality. ... Our results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system."
Tuesday, February 5, 2019
New fly model of mitochondrial disease
Lovero D, Giordano L, Marsano RM, Sanchez-Martinez A, Boukhatmi H, Drechsler M, Oliva M, Whitworth AJ, Porcelli D, Caggese C. Characterization of Drosophila ATPsynC mutants as a new model of mitochondrial ATP synthase disorders. PLoS One. 2018 Aug 10;13(8):e0201811. doi: 10.1371/journal.pone.0201811. eCollection 2018. PMID: 30096161; PMCID: PMC6086398.
From the abstract: "Mitochondrial disorders associated with genetic defects of the ATP synthase are among the most deleterious diseases of the neuromuscular system that primarily manifest in newborns. Nevertheless, the number of established animal models ... is limited. In this paper, we target the Drosophila melanogaster gene encoding for the ATP synthase subunit c, ATPsynC ... we isolated a set of mutations showing a wide range of effects, from larval lethality to complex pleiotropic phenotypes ... ATPsynC mutations impair ATP synthesis and mitochondrial morphology, and represent a powerful toolkit for the screening of genetic modifiers that can lead to potential therapeutic solutions. Furthermore, the molecular characterization of ATPsynC mutations allowed us ... to define three broad pathological consequences of mutations affecting the mitochondrial ATP synthase functionality in Drosophila: i) pre-adult lethality; ii) multi-trait pathology accompanied by early adult lethality; iii) multi-trait adult pathology. We finally predict plausible parallelisms with genetic defects of mitochondrial ATP synthase in humans."
From the abstract: "Mitochondrial disorders associated with genetic defects of the ATP synthase are among the most deleterious diseases of the neuromuscular system that primarily manifest in newborns. Nevertheless, the number of established animal models ... is limited. In this paper, we target the Drosophila melanogaster gene encoding for the ATP synthase subunit c, ATPsynC ... we isolated a set of mutations showing a wide range of effects, from larval lethality to complex pleiotropic phenotypes ... ATPsynC mutations impair ATP synthesis and mitochondrial morphology, and represent a powerful toolkit for the screening of genetic modifiers that can lead to potential therapeutic solutions. Furthermore, the molecular characterization of ATPsynC mutations allowed us ... to define three broad pathological consequences of mutations affecting the mitochondrial ATP synthase functionality in Drosophila: i) pre-adult lethality; ii) multi-trait pathology accompanied by early adult lethality; iii) multi-trait adult pathology. We finally predict plausible parallelisms with genetic defects of mitochondrial ATP synthase in humans."
Thursday, January 31, 2019
Fly models of metabolic disorders that induce seizures used to study potential positive impact of ketogenic diet
Fogle KJ, Smith AR, Satterfield SL, Gutierrez AC, Hertzler JI, McCardell CS, Shon JH, Barile ZJ, Novak MO, Palladino MJ. Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy. Mol Genet Metab. 2019 Jan 17. PMID: 30683556.
From the abstract: "Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, ... We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. ... Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder ..."
From the abstract: "Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, ... We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. ... Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder ..."
Monday, April 2, 2018
New fly model of mitochondrial disease associated with disruption of SLC25A46
1: Suda K, Ueoka I, Azuma Y, Muraoka Y, Yoshida H, Yamaguchi M. Novel Drosophila model for mitochondrial diseases by targeting of a solute carrier protein SLC25A46. Brain Res. 2018 Mar 28. pii: S0006-8993(18)30163-X. PMID: 29604258.
From the abstract: "Mutations in SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy and Leigh syndrome. Human SLC25A46 functions as a transporter across the outer mitochondrial membrane. However, it is still unknown how the neurodegeneration occurring in these diseases relates to the loss of SLC25A46 function. Drosophila has CG5755 (dSLC25A46) as a single human SLC25A46 homolog. Here we established pan-neuron specific dSLC25A46 knockdown flies, and examined their phenotypes. ... The dSLC25A46 knockdown fly ... recapitulates most of the phenotypes in mitochondrial disease patients, providing a useful tool to study these diseases."
From the abstract: "Mutations in SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy and Leigh syndrome. Human SLC25A46 functions as a transporter across the outer mitochondrial membrane. However, it is still unknown how the neurodegeneration occurring in these diseases relates to the loss of SLC25A46 function. Drosophila has CG5755 (dSLC25A46) as a single human SLC25A46 homolog. Here we established pan-neuron specific dSLC25A46 knockdown flies, and examined their phenotypes. ... The dSLC25A46 knockdown fly ... recapitulates most of the phenotypes in mitochondrial disease patients, providing a useful tool to study these diseases."
Thursday, April 6, 2017
Parallel studies in human induced pluripotent stem cells and Drosophila identify a potential new target for development of possible therapies for Parkinson's Disease
Zanon A, Kalvakuri S, Rakovic A, Foco L, Guida M, Schwienbacher C, Serafin A, Rudolph F, Trilck M, Grünewald A, Stanslowsky N, Wegner F, Giorgio V, Lavdas AA, Bodmer R, Pramstaller PP, Klein C, Hicks AA, Pichler I, Seibler P. SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet. 2017 Apr 3. PMID: 28379402.
From the abstract: "Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. ... In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes ... The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies."
From the abstract: "Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. ... In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes ... The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies."
Tuesday, December 27, 2016
Review: Fly model in evaluation of therapeutics for mitochondrial diseases
Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol. 2015 Jun;63:60-5. PMID: 25666557.
From the abstract: "... mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. ... Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. ... Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery ..."
From the abstract: "... mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. ... Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. ... Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery ..."
Friday, October 23, 2015
Report of new insights into mitochondrial retrograde signaling and its impact in Leigh syndrome and Parkinson's and other neurodegenerative diseases
Cagin U, Duncan OF, Gatt AP, Dionne MS, Sweeney ST, Bateman JM. Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A. 2015 Oct 21. pii: 201505036. PMID: 26489648.
From the abstract: "Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. ... We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. ..."
From the abstract: "Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. ... We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. ..."
Wednesday, June 17, 2015
Fly study results suggest limitations to usefulness of a potential treatment for mitochondrial disorders
Kemppainen KK, Kemppainen E, Jacobs HT. The alternative oxidase AOX does not rescue the phenotype of tko25t mutant flies. G3 (Bethesda). 2014 Aug 21;4(10):2013-21. PMID: 25147191; PMCID: PMC4199707.
From the abstract: "A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases ... Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes ... We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) ... We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value."
From the abstract: "A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases ... Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes ... We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) ... We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value."
Wednesday, June 3, 2015
New fly model related to mitochondrial diseases
Holmbeck MA, Donner JR, Villa-Cuesta E, Rand DM. A Drosophila model for mito-nuclear diseases generated by an incompatible tRNA-tRNA synthetase interaction. Dis Model Mech. 2015 May 5. pii: dmm.019323. PMID: 26035388.
From the abstract: "... Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function."
From the abstract: "... Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function."
Monday, March 2, 2015
Review of fly models of mitochondrial diseases
Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol. 2015 Feb 7. pii: S1357-2725(15)00034-5. PMID: 25666557.
From the abstract: "... mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. ... Despite intense research efforts, patients are still without effective treatment. ... Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery."
From the abstract: "... mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. ... Despite intense research efforts, patients are still without effective treatment. ... Here, we review existing Drosophila melanogaster models for mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery."
Tuesday, August 26, 2014
Review--invertebrate models of coenzyme Q disease
Fernández-Ayala DJ, Jiménez-Gancedo S, Guerra I, Navas P. Invertebrate models for coenzyme q10 deficiency. Mol Syndromol. 2014 Jul;5(3-4):170-9. PMID: 25126050; PMCID: PMC4112529.
Tuesday, August 5, 2014
Drosophila model of complex I dysfunction-type mitochondrial disease
Burman JL, Itsara LS, Kayser EB, Suthammarak W, Wang AM, Kaeberlein M, Sedensky MM, Morgan PG, Pallanck LJ. A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer. Dis Model Mech. 2014 PMID: 25085991.
From the abstract: "Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-encoded NADH dehydrogenase subunit 2 (ND2) gene. ... our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex I-associated neurodegeneration."
From the abstract: "Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-encoded NADH dehydrogenase subunit 2 (ND2) gene. ... our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex I-associated neurodegeneration."
Sunday, July 20, 2014
Succinate Dehydrogenase-related neurodegeneration and cancers--study in yeast, flies and mammalian cells
Van Vranken JG, Bricker DK, Dephoure N, Gygi SP, Cox JE, Thummel CS, Rutter J. SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration. Cell Metab. 2014 Jun 18. pii: S1550-4131(14)00220-4. PMID: 24954416.
From the abstract: "Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize an evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. ... These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor."
From the abstract: "Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize an evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. ... These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor."
Sunday, March 30, 2014
Flies, zinc binding, mitochondria and ALS
Bahadorani S, Mukai ST, Rabie J, Beckman JS, Phillips JP, Hilliker AJ. Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction. Neurobiol Aging. 2013 Oct;34(10):2322-30. PMID: 23601674.
Tuesday, February 4, 2014
From patient mutation to model fly: study related to mitochondrial function and disease
van Bon BW, Oortveld MA, Nijtmans LG, Fenckova M, Nijhof B, Besseling J, Vos M, Kramer JM, de Leeuw N, Castells-Nobau A, Asztalos L, Viragh E, Ruiter M, Hofmann F, Eshuis L, Collavin L, Huynen MA, Asztalos Z, Verstreken P, Rodenburg RJ, Smeitink JA, de Vries BB, Schenck A. CEP89 is required for mitochondrial metabolism and neuronal function in man and fly. Hum Mol Genet. 2013 Aug1;22(15):3138-51. PMID: 23575228.
From the abstract: "We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. ... these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. ... We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution."
From the abstract: "We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. ... these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. ... We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution."
Tuesday, January 28, 2014
Mitochondrial disease and the fly
Kemppainen KK, Rinne J, Sriram A, Lakanmaa M, Zeb A, Tuomela T, Popplestone A, Singh S, Sanz A, Rustin P, Jacobs HT. Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency. Hum Mol Genet. 2013 Dec 16. PMID: 24293544.
Monday, June 3, 2013
New fly model of mitochondrial diseases related to tRNA synthetases
Guitart T, Picchioni D, Piñeyro D, Ribas de Pouplana L. Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies. Nucleic Acids Res. 2013 May 15. PMID: 23677612.
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