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Mitochondrial fusion and fission regulation in Parkinson’s Disease

Santos, Daniel Ferreira dos
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
36.58%
A doença de Parkinson é a segunda doença neurodegenerativa mais comum e a doença neurodegenerativa associada ao movimento mais comum. É causada pela perda dos neurónios dopaminérgicos na substantia nigra pars compacta levando a um défice de dopamina no estriado. Perceber a base molecular da doença de Parkinson tem se revelado um grande desafio no campo das doenças neurodegenerativas. Apesar de terem sido propostas várias hipóteses para explicar os mecanismos subjacentes a patogenia da doença de Parkinson, um crescente corpo de evidencias tem enfatizado o papel da disrupção da dinâmica mitocôndrial como um grande contribuidor para a etiopatogenia da doença de Parkinson. Tem se vindo a acumular dados que sugerem que uma dinâmica mitocondrial anormal se encontra envolvida na disfunção mitocôndrial ou medeia a morte neuronal em diferentes modelos da doença de Parkinson. Aliás, a integração da fissão, fusão e autofagia mitocondrial forma um mecanismo de manutenção de qualidade mitocôndrial da homeostase mitocôndrial na qual defeitos na função mitocôndrial têm sido associados à doença de Parkinson. A maioria dos casos surge como condição esporádica e os restantes são herdados com mutações em vários genes que tem sido ligados a essas formas genéticas da doença. Os estudos de duas das proteínas ligadas as formas familiares da doença...

Mitochondrial signaling pathway in Alzheimer´s disease: disclosure of new therapeutic targets

Silva, Diana Filipa Ferreira da
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.55%
The etiology of sporadic Alzheimer´s disease remains largely unknown. Data from literature show that a bioenergetics failure, especially due to mitochondrial dysfunction, is a common event in Alzheimer’s disease and mild cognitive impairment, a clinical syndrome that frequently precedes symptomatic Alzheimer´s disease. Mitochondria play a pivotal role in cellular metabolism since they regulate key aspects of cellular metabolism by ATP production, also have important functions in intracellular calcium homeostasis, endogenous reactive oxygen species production and decide cellular fate by regulating programmed cell death. The use of cytoplasmic hybrid cell lines that contain mitochondria from Alzheimer´s disease and mild cognitive impairment subjects allow to infer that mitochondrial dysfunction, through complex IV decreased activity, are an upstream event in the pathology of Alzheimer´s disease. Further, the transfer of mitochondria from Alzheimer´s disease subjects, mild cognitive impairment and control subjects to mtDNA depleted cells enable to study downstream events driven by mitochondrial dysfunction. Previous studies using Alzheimer´s disease cybrids showed decreased complex IV, we extended these results by showing that in mild cognitive impairment cybrids complex IV dysfunction is also present. Besides decreased complex IV activity...

Mitochondrial Swelling and Incipient Outer Membrane Rupture in Preapoptotic and Apoptotic Cells

Sesso, A.; Belizario, J. E.; Marques, M. M.; Higuchi, M. L.; Schumacher, R. I.; Colquhoun, A.; Ito, E.; Kawakami, J.
Fonte: WILEY-BLACKWELL; HOBOKEN Publicador: WILEY-BLACKWELL; HOBOKEN
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.52%
Outer mitochondrial membrane (OMM) rupture was first noted in isolated mitochondria in which the inner mitochondrial membrane (IMM) had lost its selective permeability. This phenomenon referred to as mitochondrial permeability transition (MPT) refers to a permeabilized inner membrane that originates a large swelling in the mitochondrial matrix, which distends the outer membrane until it ruptures. Here, we have expanded previous electron microscopic observations that in apoptotic cells, OMM rupture is not caused by a membrane stretching promoted by a markedly swollen matrix. It is shown that the widths of the ruptured regions of the OMM vary from 6 to 250 nm. Independent of the perforation size, herniation of the mitochondrial matrix appeared to have resulted in pushing the IMM through the perforation. A large, long focal herniation of the mitochondrial matrix, covered with the IMM, was associated with a rupture of the OMM that was as small as 6 nm. Contextually, the collapse of the selective permeability of the IMM may precede or follow the release of the mitochondrial proteins of the intermembrane space into the cytoplasm. When the MPT is a late event, exit of the intermembrane space proteins to the cytoplasm is unimpeded and occurs through channels that transverse the outer membrane...

Efeitos da restrição calórica nas vias de sinalização por insulina e óxido nítrico: implicações para biogênese, morfologia e função mitocondriais; Calorie restriction restriction effects on insulin and nitric oxide signaling: implications to mitochondrial biogenesis, morphology and function.

Cerqueira, Fernanda Menezes
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 27/02/2012 Português
Relevância na Pesquisa
36.52%
A restrição calórica (RC) estende a expectativa de vida de muitos organismos por mecanismos ainda em estudo. Entre os vários efeitos fisiológicos da RC encontra-se o aumento na biogênese mitocondrial, dependente de óxido nítrico (NO•), sintetizado pela enzima óxido nítrico sintase endotelial (eNOS). Um dos indutores fisiológicos mais potentes da eNOS é a insulina, cujos níveis plasmáticos são consideravelmente reduzidos nos organismos em RC. O objetivo deste trabalho foi investigar os mecanismos associados ao aumento da sinalização por NO• durante a RC in vivo e in vitro, e as conseqüências celulares do aumento de massa mitocondrial no que diz respeito à longevidade e capacidade respiratória celulares. Submetemos camundongos Swiss fêmeas à RC de 40% e observamos um considerável aumento tecido-específico na fosforilação basal de Akt e eNOS em músculo esquelético, tecido adiposo visceral e cérebro, os quais também apresentaram maior massa mitocondrial. A associação entre a sinalização por insulina, NO• e biogênese mitocondrial foi adicionalmente confirmada em um grupo de camundongos tratados com o desacoplador mitocondrial dinitrofenol (DNP), que também reduz a insulinemia e aumenta a longevidade em camundongos. Para o estudo mecanístico deste fenômeno...

Análise da mobilidade mitocondrial em células vivas do hipocampo, substância negra e locus coeruleus anterior à agregação proteica envolvida  em neurodegeneração; Analisys of mitochondrial mobility in living hippocampal, substantita nigra and locus coeruleos cells before protein aggregation involved in neurodegeneration

Martins, Stephanie Alves
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 29/11/2013 Português
Relevância na Pesquisa
36.51%
A alteração do tráfego mitocondrial em neurônios leva ao aumento do estresse oxidativo, privação de energia, deficiência da comunicação intercelular e neurodegeneração. Há evidências de que essas alterações de tráfego antecedem a morte neuronal associada à agregação proteica. Portanto, conhecer a relação entre a mobilidade mitocondrial e a formação de agregados proteicos pode ser um passo importante para o melhor entendimento dos mecanismos da neurodegeneração. Com isso, o objetivo do presente estudo é analisar a mobilidade das mitocôndrias em culturas de células do hipocampo, substância negra e locus coeruleus expostas a rotenona e MPTP, como agentes neurodegenerativos, e à rapamicina como ativador da autofagia. Um outro objetivo do estudo é avaliar o papel do cálcio (através do emprego de EGTA e ionomicina) no modelo experimental. Os resultados mostraram aumento da mobilidade mitocondrial no hipocampo e diminuição na substância negra, já no locus coeruleus houve aumento seguido de diminuição da mobilidade mitocondrial dependendo da concentração de rotenona. O emprego do EGTA e ionomicina mostra que a ação da rotenona sobre o tráfego mitocondrial envolve o cálcio, mas não se relaciona com uma possível alteração da integridade mitocondrial...

Alterações no metabolismo energético provocadas pela superexpressão da proteína desacopladora mitocondrial 1 (UCP1) em tabaco induzem biogênese mitocondrial e resposta global a estresses = : Alterations on energy metabolism caused by mitochondrial uncoupling protein 1 (UCP1) overexpression in tobacco induce mitochondrial biogenesis and global stress response; Alterations on energy metabolism caused by mitochondrial uncoupling protein 1 (UCP1) overexpression in tobacco induce mitochondrial biogenesis and global stress response

Pedro Paulo Augusto Fabiano Arantes Pereira Barreto
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 31/07/2014 Português
Relevância na Pesquisa
36.54%
A proteína desacopladora mitocondrial 1 (UCP1) é uma proteína mitocondrial codificada pelo núcleo capaz de desacoplar o gradiente eletroquímico usado para a síntese de ATP, dissipando a energia na forma de calor. A descoberta de homólogos e ortólogos da UCP1, sugere outros papéis fisiológicos para estas proteínas. As UCPs podem servir como uma válvula de escape, diminuindo a força protonmotiva (PMF) e reduzindo a produção de ROS em condições desfavoráveis. Plantas superexpressando UCPs se desenvolvem melhor quando submetidas a estresses bióticos e abióticos. Estas plantas demonstraram diminuição na produção de ROS, alteração no estado redox celular, além de um aumento no metabolismo energético e na fotossíntese. Neste trabalho nós investigamos os mecanismos moleculares envolvidos no metabolismo energético celular e resposta a estresses em plantas de tabaco superexpressando a UCP1 de A. thaliana. Demonstramos, através de análises moleculares e genômicas, que a superexpressão da UCP1 é capaz de provocar o aumento na respiração desacoplada em mitocôndrias isoladas, diminuir o conteúdo de ATP intracelular, e desencadear um processo de sinalização retrógrada que resulta na indução de genes mitocondriais e genes responsivos a estresses. Esta sinalização retrógrada resultou na indução do processo de biogênese mitocondrial verificado pelo aumento no número e área mitocondrial por célula...

The mitochondrial genome of the pinewood nematode (Bursaphelenchus xylophilus) lineage introduced in Europe

Moreira, Claudia; Asch, Barbara; Fonseca, Luis; Pereira-Castro, Isabel; Silva, Raquel; Azevedo, Luísa; Mota, Manuel; Abrantes, Isabel; Amorim, António; Pereira, Filipe
Fonte: Mitochondrial DNA Publicador: Mitochondrial DNA
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.34%
The pinewood nematode (PWN) Bursaphelenchus xylophilus is the causative agent of pine wilt disease and the greatest biological threat to conifer forests worldwide. Here we describe the near-complete mitochondrial DNA (mtDNA) sequence (12,945 bp) of the PWN lineage recently introduced in Europe. The absence of polymorphisms across the mtDNA of three Portuguese isolates suggests that a single mitochondrial lineage was introduced in southwestern Europe. We also found that Portuguese isolates have an incomplete stop codon (TA) at COX3, while the reference mtDNA from a South Korean isolate has a complete stop codon (TAA). Moreover, two insertion/deletion polymorphisms change the ND4 protein in a stretch of seven amino acids, and a polymorphic mononucleotide repeat alters the predicted structure of the tyrosine tRNA in different geographical isolates. Overall, the new PWN mtDNA sequence provides a basis for studying the European dispersion of this important invasive species.

Chronically elevated glucose compromises myocardial mitochondrial DNA integrity by alteration of mitochondrial topoisomerase function

Medikayala, S.; Piteo, B.; Zhao, X.; Edwards, J. G.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.51%
Mitochondrial dysfunction has a significant role in the development and complications of diabetic cardiomyopathy. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) mutations are also associated with different types of cancer and neurodegenerative diseases. The goal of this study was to determine if chronically elevated glucose increase in mtDNA damage contributed to mitochondrial dysfunction and identify the underlying basis for mtDNA damage. H9c2 myotubes (a cardiac-derived cell line) were studied in the presence of 5.5, 16.5, or 33.0 mM glucose for up to 13 days. Tests of mitochondria function (Complex I and IV activity and ATP generation) were all significantly depressed by elevated media glucose. Intramitochondrial superoxide and intracellular superoxide levels were transiently increased during the experimental period. AnnexinV binding (a marker of apoptosis) was significantly increased after 7 and 13 days of high glucose. Thirteen days of elevated glucose significantly increased mtDNA damage globally and across the region encoding for the three subunits of cytochrome oxidase. Using mitochondria isolated from cells chronically exposed to elevated glucose, we observed significant increases in topoisomerase-linked DNA cleavage. Mitochondria-dependent DNA cleavage was significantly exacerbated by H2O2 and that immunoprecipitation of mitochondrial extracts with a mtTOP1 antibody significantly decreased DNA cleavage...

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function

Seo, Young Ah; Lopez, Veronica; Kelleher, Shannon L.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.51%
Female reproductive tissues such as mammary glands, ovaries, uterus, and placenta are phenotypically dynamic, requiring tight integration of bioenergetic and apoptotic mechanisms. Mitochondrial zinc (Zn) pools have emerged as a central player in regulating bioenergetics and apoptosis. Zn must first be imported into mitochondria to modulate mitochondrion-specific functions; however, mitochondrial Zn import mechanisms have not been identified. Here we documented that the Zn transporter ZnT2 is associated with the inner mitochondrial membrane and acts as an auxiliary Zn importer into mitochondria in mammary cells. We found that attenuation of ZnT2 expression significantly reduced mitochondrial Zn uptake and total mitochondrial Zn pools. Moreover, expression of a ZnT2-hemagglutinin (HA) fusion protein was localized to mitochondria and significantly increased Zn uptake and mitochondrial Zn pools, directly implicating ZnT2 in Zn import into mitochondria. Confocal microscopy of truncated and point mutants of ZnT2-green fluorescent protein (GFP) fusion proteins revealed a histidine-rich motif (51HHXH54) in the NH2 terminus that is important for mitochondrial targeting of ZnT2. More importantly, the expansion of mitochondrial Zn pools by ZnT2 overexpression significantly reduced ATP biogenesis and mitochondrial oxidation concurrent with increased apoptosis...

Gem1 and ERMES Do Not Directly Affect Phosphatidylserine Transport from ER to Mitochondria or Mitochondrial Inheritance

Nguyen, Tammy T; Lewandowska, Agnieszka; Choi, Jae-Yeon; Markgraf, Daniel F; Junker, Mirco; Bilgin, Mesut; Ejsing, Christer S; Voelker, Dennis R; Rapoport, Tom A; Shaw, Janet M
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.52%
In yeast, a protein complex termed the ER-Mitochondria Encounter Structure (ERMES) tethers mitochondria to the endoplasmic reticulum. ERMES proteins are implicated in a variety of cellular functions including phospholipid synthesis, mitochondrial protein import, mitochondrial attachment to actin, polarized mitochondrial movement into daughter cells during division, and maintenance of mitochondrial DNA (mtDNA). The mitochondrial-anchored Gem1 GTPase has been proposed to regulate ERMES functions. Here, we show that ERMES and Gem1 have no direct role in the transport of phosphatidylserine (PS) from the ER to mitochondria during the synthesis of phosphatidylethanolamine (PE), as PS to PE conversion is not affected in ERMES or gem1 mutants. In addition, we report that mitochondrial inheritance defects in ERMES mutants are a secondary consequence of mitochondrial morphology defects, arguing against a primary role for ERMES in mitochondrial association with actin and mitochondrial movement. Finally, we show that ERMES complexes are long-lived, and do not depend on the presence of Gem1. Our findings suggest that the ERMES complex may have primarily a structural role in maintaining mitochondrial morphology.

Identification of novel molecular interactions of the mitochondrial fission protein hFis1 : insight into its action mechanism and therapeutic potential

Serasinghe, Madhavika Niroshini ; Yoon, Yisang ; Gunter, Thomas E.
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.55%
Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biochemistry and Biophysics, 2009.; Mitochondria are dynamic cellular organelles that undergo continuous shape changes within the cell. Two major processes are responsible for the dynamics of mitochondria, namely fission and fusion. A balance of these two opposing events is thought to maintain the normal mitochondrial phenotype in a given cell under normal conditions. Shifting of this balance either way results in abnormal mitochondrial morphologies that are often linked to abnormalities in mitochondrial function and in extreme cases certain disease conditions. Therefore, it has been suggested that mitochondrial dynamics is an important factor in maintaining healthy mitochondria and normal cellular function. The current study investigates the fission process in mammalian mitochondria with specific focus on defining novel molecular interactions of the fission protein hFis1. hFis1 is a mitochondrial outer membrane protein of 17 kDa that acts as a receptor for the cytosolic large GTPase DLP1, which assembles on the outer membrane and constricts the mitochondrial tubules through GTP hydrolysis, bringing about the fission of mitochondria. hFis1 contains six α helices in its N-terminal cytosolic domain...

Regulation of Mitochondrial Morphology by Intracellular Calcium in Liver and Heart Cells

Hom, Jennifer ; Sheu, Shey-shing
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.59%
Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Pharmacology and Physiology, 2009.; Mitochondrial fission and fusion mediate the dynamic change of mitochondrial morphology in the living cell. Increasing evidence indicates that mitochondria change morphology in response to certain cellular demands, and that maintaining correct mitochondrial morphology is important for cell function. The protein factors that directly participate in mitochondrial dynamics are well known. However, the upstream signals that regulate mitochondrial morphology were not well understood and have only recently come to the forefront. Given that Ca2+ is the central component in the regulation of mitochondrial function such as ATP generation, redox control, and apoptosis, I hypothesized that intracellular Ca2+ is the signal that regulates mitochondrial morphology. To test this hypothesis, I treated the Clone 9 liver cell line with the ER Ca2+-ATPase inhibitor thapsigargin (TG), which induced a biphasic mitochondrial fragmentation. The initial mitochondrial fragmentation occurred rapidly and transiently, and depended on the increase of cytosolic Ca2+ and mitochondrial Ca2+ uptake. This fragmentation reversed when the Ca2+ level decreased. Moreover...

Regulation of Mitochondrial Morphology by Intracellular Calcium in Liver and Heart Cells

Hom, Jennifer ; Sheu, Shey-shing
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.59%
Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Pharmacology and Physiology, 2009.; Mitochondrial fission and fusion mediate the dynamic change of mitochondrial morphology in the living cell. Increasing evidence indicates that mitochondria change morphology in response to certain cellular demands, and that maintaining correct mitochondrial morphology is important for cell function. The protein factors that directly participate in mitochondrial dynamics are well known. However, the upstream signals that regulate mitochondrial morphology were not well understood and have only recently come to the forefront. Given that Ca2+ is the central component in the regulation of mitochondrial function such as ATP generation, redox control, and apoptosis, I hypothesized that intracellular Ca2+ is the signal that regulates mitochondrial morphology. To test this hypothesis, I treated the Clone 9 liver cell line with the ER Ca2+-ATPase inhibitor thapsigargin (TG), which induced a biphasic mitochondrial fragmentation. The initial mitochondrial fragmentation occurred rapidly and transiently, and depended on the increase of cytosolic Ca2+ and mitochondrial Ca2+ uptake. This fragmentation reversed when the Ca2+ level decreased. Moreover...

Mitochondrial Membrane Fusion, pH Homeostasis and ROS Signaling in Caenorhabditis elegans

Johnson, David W. ; Nehrke, Keith ; Munger, Joshua
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.54%
Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biochemistry, 2010.; The ability to regulate intracellular pH (pHi) is essential for viability. In addition to well-recognized roles in maintaining cellular homeostasis and functions related to fluid and electrolyte balance, proteins that contribute to pHi regulation can also participate in acute signaling processes both within and between cells. For example, our results have demonstrated that the sodium-proton exchanger NHX-7 extrudes protons during a rhythmic behavior in worms. These protons are a direct ligand for a receptor on adjacent muscle cells and trigger muscle contraction. This is the first example of a sodium proton exchanger being involved in transmitting information between cells. Together with the recent identification of several classes of proteins that are sensitive to extracellular acidification in both worms and mammals, this represents a conserved signaling pathway with potentially widespread significance. To further identify proteins that affect pHi, a large-scale RNA interference (RNAi) screen was performed in the genetic model organism C. elegans. The screen resulted in forty-five targets whose loss reliably reduced intestinal pHi following inactivation. Further analysis revealed that genes which have putative or known mitochondrial function are three-fold over-represented in this population (9/45 or 20%) compared to the genome as a whole (719/~20...

Characterization of 67 Mitochondrial tRNA Gene Rearrangements in the Hymenoptera Suggests That Mitochondrial tRNA Gene Position Is Selectively Neutral

Dowton, M.; Cameron, S.; Dowavic, J.; Austin, A.; Whiting, M.
Fonte: Oxford Univ Press Publicador: Oxford Univ Press
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
Relevância na Pesquisa
36.55%
We present entire sequences of two hymenopteran mitochondrial genomes and the major portion of three others. We combined these data with nine previously sequenced hymenopteran mitochondrial genomes. This allowed us to infer and analyze the evolution of the 67 mitochondrial gene rearrangements so far found in this order. All of these involve tRNA genes, whereas four also involve larger (protein-coding or ribosomal RNA) genes. We find that the vast majority of mitochondrial gene rearrangements are independently derived. A maximum of four of these rearrangements represent shared, derived organizations, whereas three are convergently derived. The remaining mitochondrial gene rearrangements represent new mitochondrial genome organizations. These data are consistent with the proposal that there are an enormous number of alternative mitochondrial genome organizations possible and that mitochondrial genome organization is, for the most part, selectively neutral. Nevertheless, some mitochondrial genes appear less mobile than others. Genes close to the noncoding region are generally more mobile but only marginally so. Some mitochondrial genes rearrange in a pattern consistent with the duplication/random loss model, but more mitochondrial genes move in a pattern inconsistent with this model. An increased rate of mitochondrial gene rearrangement is not tightly associated with the evolution of parasitism. Although parasitic lineages tend to have more mitochondrial gene rearrangements than nonparasitic lineages...

Estudo dos mecanismos moleculares do reparo de quebra de duplas fitas no DNA mitocondrial; Study of the molecular mechanisms of double-strand break repair in mitochondrial DNA

Santos, Valquiria Tiago dos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 08/05/2015 Português
Relevância na Pesquisa
36.52%
O DNA está constantemente exposto a danos causados tanto por agentes endógenos quanto exógenos. Estes podem causar diferentes tipos de lesões incluindo modificações de bases e do açúcar, além de quebras de fitas simples ou duplas. As quebras de duplas fitas, quando comparadas às demais, constituem as mais citotóxicas e podem resultar em deleções no DNA e instabilidade genética. Deleções no DNA mitocondrial (mtDNA) causam diversas doenças e estão envolvidas no processo de envelhecimento. No núcleo, as quebras de duplas fitas no DNA podem ser reparadas por recombinação homóloga (HR), ligação de pontas não homólogas (NHEJ) e anelamento de fita simples (SSA). No entanto, em mitocôndrias de células de mamíferos, o reparo de quebras de duplas fitas ainda não foi completamente caracterizado. Experimentos in vitro usando extratos mitocondriais de células de roedores mostraram que estes são capazes de reparar essas quebras, no entanto pouco é sabido sobre quais proteínas são responsáveis por cada etapa de reparo, bem como sua implicação na manutenção da integridade do genoma mitocondrial. Sendo assim, nesse trabalho investigamos a localização e função mitocondrial das proteínas ATM, Rad51, Rad52...

ENVIRONMENTAL SENSITIVITY OF MITOCHONDRIAL GENE EXPRESSION IN FISH

BREMER, KATHARINA
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
36.56%
Maintaining energy organismal homeostasis under changing physiological and environmental conditions is vital, and requires constant adjustments of the energy metabolism. Central to meeting energy demands is the regulation of mitochondrial oxidative capacity. When demands increase, animals can increase mitochondrial content/enzymes, known as mitochondrial biogenesis. Central to mammalian mitochondrial biogenesis is the transcriptional master regulator PPARγ (peroxisome proliferator-activated receptor γ) coactivator-1α (PGC-1α), and the network of DNA-binding proteins it coactivates (e.g. nuclear respiratory factor 1 and 2 [NRF-1, NRF-2], estrogen-related receptor α [ERRα], thyroid receptor α [TRα-1], retinoid X receptor α [RXRα]). However, the mechanisms by which mitochondrial content in lower vertebrates such as fish is controlled are less studied. In my study I investigate underlying mechanisms of the phenomenon that many fish species alter mitochondrial enzyme activities, such as cytochrome c oxidase (COX) in response to low temperatures. In particular, I investigated (i) if the phenomenon of mitochondrial biogenesis during cold-acclimation is related to fish phylogeny, (ii) what role PGC-1α and other transcription factors play in mitochondrial biogenesis in fish...

Disruption of Mitochondrial Dynamics in Tauopathy

DuBoff, Brian Michael
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
Relevância na Pesquisa
36.55%
Alzheimer’s disease (AD) is characterized pathologically by proteinaceous aggregates composed primarily of amyloid \(\beta (A \beta)\) and tau. Diseases characterized by abnormal deposition of tau are collectively termed “tauopathies.” \(A \beta\) acts upstream of tau in the AD pathogenesis pathway, but tau expression is required for the neurodegenerative effects of \(A \beta\). Mitochondrial abnormalities have been documented in Alzheimer’s disease and related tauopathies, but the causal relationship between mitochondrial changes and neurodegeneration, as well as specific mechanisms promoting mitochondrial dysfunction, are unclear. Mitochondrial morphology is regulated by fission and fusion events within and between individual mitochondria, and misregulation of this process has been observed in several neurodegenerative diseases. The contribution of mitochondrial dynamics to the pathogenesis of Alzheimer’s disease and tauopathy has not yet been determined. We have found that expression of tau promotes elongation of mitochondria in Drosophila and vertebrate neurons. Elongation is followed by mitochondrial dysfunction, aberrant cell cycle reactivation, and cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. Tau induces mitochondrial elongation by inhibiting mitochondrial localization of DRP1...

Unravelling mitochondrial pathways to Parkinson's disease

Celardo, I; Martins, L M; Gandhi, S
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.52%
Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm...

Role of Mitochondrial Dynamics and Autophagy in Removal of Helix-Distorting Mitochondrial DNA Damage

Bess, Amanda Smith
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2012 Português
Relevância na Pesquisa
36.56%

Mitochondria are the primary energy producers of the cell and play key roles in cellular signaling, apoptosis and reactive oxygen species (ROS) production. Mitochondria are the only organelles that contain their own genome which encodes for a small subset of electron transport chain (ETC) proteins as well as the necessary tRNAs and ribosomal subunits to translate these proteins. Over 300 pathogenic mitochondrial DNA (mtDNA) mutations have been shown to cause a number of mitochondrial diseases emphasizing the importance of mtDNA maintenance and integrity to human health. Additionally, mitochondrial dysfunction and mtDNA instability are linked to many wide-spread diseases associated with aging including cancer and neurodegeneration. Mitochondria lack the ability to repair certain helix-distorting lesions that are induced at high levels in mtDNA by important environmental genotoxins including polycyclic aromatic hydrocarbons, ultraviolet C radiation (UVC) and mycotoxins. These lesions are irreparable and persistent in the short term, but their long-term fate is unknown. Degradation of mitochondria and mtDNA is carried out by autophagy. Autophagy is protective against cell stress and apoptosis resulting from exposure to mitochondrial toxicants suggesting that it plays an important role in removal of unstable mitochondria that can serve as a source of ROS or initiate apoptotic cell death. Furthermore...