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Dive into the research topics where Alexandra Götz is active.

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Featured researches published by Alexandra Götz.


PLOS Medicine | 2008

Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity

Kirsi H. Pietiläinen; Jussi Naukkarinen; Aila Rissanen; Juha Saharinen; Pekka Ellonen; Heli Keränen; Anu Suomalainen; Alexandra Götz; Tapani Suortti; Hannele Yki-Järvinen; Matej Orešič; Jaakko Kaprio; Leena Peltonen

Background The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background. Methods and Findings We used a special study design of “clonal controls,” rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/m2. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twins fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults. Conclusions Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.


Cell Metabolism | 2012

Somatic Progenitor Cell Vulnerability to Mitochondrial DNA Mutagenesis Underlies Progeroid Phenotypes in Polg Mutator Mice

Kati Ahlqvist; Riikka H. Hämäläinen; Shuichi Yatsuga; Marko Uutela; Mügen Terzioglu; Alexandra Götz; Saara Forsström; Petri Salven; Alexandre Angers-Loustau; Outi Kopra; Henna Tyynismaa; Nils-Göran Larsson; Kirmo Wartiovaara; Tomas A. Prolla; Aleksandra Trifunovic; Anu Suomalainen

Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L-cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations.


Brain | 2008

Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome

Alexandra Götz; Pirjo Isohanni; Helena Pihko; Anders Paetau; Riitta Herva; Outi Saarenpää-Heikkilä; Leena Valanne; Sanna Marjavaara; Anu Suomalainen

Mitochondrial DNA depletion syndrome (MDS) is a severe recessively inherited disease of childhood. It manifests most often in infancy, is rapidly progressive and leads to early death. MDS is caused by an increasing number of nuclear genes leading to multisystemic or tissue-specific decrease in mitochondrial DNA (mtDNA) copy number. Thymidine kinase 2 (TK2) has been reported to cause a myopathic form of MDS. We report here the clinical, autopsy and molecular genetic findings of rapidly progressive fatal infantile mitochondrial syndrome. All of our seven patients had rapidly progressive myopathy/encephalomyopathy, leading to respiratory failure within the first 3 years of life, with high creatine kinase values and dystrophic changes in the muscle with cytochrome c oxidase-negative fibres. In addition, two patients also had terminal-phase seizures, one had epilepsia partialis continua and one had cortical laminar necrosis. We identified two different homozygous or compound heterozygous mutations in the TK2 gene in all the patients: c.739 C s -> T and c.898 C -> T, leading to p.R172W and p.R225W changes at conserved protein sites. R172W mutation led to myopathy or encephalomyopathy with the onset during the first months of life, and was associated with severe mtDNA depletion in the muscle, brain and liver. Homozygosity for R225W mutation manifested during the second year of life as a myopathy, and showed muscle-specific mtDNA depletion. Both mutations originated from single ancient founders, with Finnish origin and enrichment for the new R172W mutation, and possibly Scandinavian ancestral origin for the R225W. We conclude that TK2 mutations may manifest as infantile-onset fatal myopathy with dystrophic features, but should be considered also in infantile progressive encephalomyopathy with wide-spread mtDNA depletion.


Journal of Medical Genetics | 2013

Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy

Christopher J. Carroll; Pirjo Isohanni; Rosanna Pöyhönen; Liliya Euro; Uwe Richter; Virginia Brilhante; Alexandra Götz; Taina Lahtinen; Anders Paetau; Helena Pihko; Brendan J. Battersby; Henna Tyynismaa; Anu Suomalainen

Background The genetic complexity of infantile cardiomyopathies is remarkable, and the importance of mitochondrial translation defects as a causative factor is only starting to be recognised. We investigated the genetic basis for infantile onset recessive hypertrophic cardiomyopathy in two siblings. Methods and results Analysis of respiratory chain enzymes revealed a combined deficiency of complexes I and IV in the heart and skeletal muscle. Exome sequencing uncovered a homozygous mutation (L156R) in MRPL44 of both siblings. MRPL44 encodes a protein in the large subunit of the mitochondrial ribosome and is suggested to locate in close proximity to the tunnel exit of the yeast mitochondrial ribosome. We found severely reduced MRPL44 levels in the patients heart, skeletal muscle and fibroblasts suggesting that the missense mutation affected the protein stability. In patient fibroblasts, decreased MRPL44 affected assembly of the large ribosomal subunit and stability of 16S rRNA leading to complex IV deficiency. Despite this assembly defect, de novo mitochondrial translation was only mildly affected in fibroblasts suggesting that MRPL44 may have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome. Retroviral expression of wild-type MRPL44 in patient fibroblasts rescued the large ribosome assembly defect and COX deficiency. Conclusions These findings indicate that mitochondrial ribosomal subunit defects can generate tissue-specific manifestations, such as cardiomyopathy.


Pediatric Research | 2012

Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine (UCN) mutation

Alexandra Götz; Pirjo Isohanni; Brita Liljeström; Jaana Rummukainen; Kari Nikolajev; Eila Herrgård; Sanna Marjavaara; Anu Suomalainen

Introduction:Heteroplasmic mitochondrial DNA (mtDNA) mutations are an important cause of childhood disorders, but the role of homoplasmic mtDNA mutations in severe neonatal manifestations is not well understood.Methods:The following were performed: full mtDNA sequencing for mutation detection, blue-native protein analysis of autopsy-derived tissues to detect respiratory chain (RC) deficiency, light and electron microscopy for morphologic analysis, and northern blot and computational modeling to study the effect of mtDNA mutations on transfer RNA (tRNA) stability.Results:We describe data from a patient with fatal neonatal lactic acidosis caused by a novel homoplasmic mutation at a highly conserved nucleotide G7453A within the tRNASer (UCN) in mtDNA. The patient’s heart, skeletal muscle, brain, and liver showed severe combined complex I and IV (CI and CIV) deficiencies, accompanied by severe depletion of mature tRNASer (UCN). The mutation was absent in the patient’s mother and in a placental sample from a subsequent pregnancy of the mother, suggesting a de novo mutation.Discussion:We conclude that the G7453A mutation of mtDNA manifests with exceptional severity as compared with other tRNASer (UCN) mutations, typically associated with sensorineural deafness. De novo homoplasmic mtDNA tRNA-mutations should be considered as a cause of fatal neonatal lactic acidosis.


Molecular Human Reproduction | 2009

Do mitochondrial mutations cause recurrent miscarriage

Milja Kaare; Alexandra Götz; Veli-Matti Ulander; Sarah Ariansen; Risto Kaaja; Anu Suomalainen; Kristiina Aittomäki

The cause of recurrent miscarriage (RM) can be identified in approximately 50% of cases, whereas in others, unknown genetic factors are actively being sought. As mitochondrial functions, and therefore also the mitochondrial genome [mitochondrial DNA (mtDNA)], have an important role in human development, through ATP production and participation in apoptosis, we aimed to study the role of mtDNA variations in RM. We screened 48 women with RM and 48 age-matched control women for heteroplasmic mitochondrial mutations using denaturing high performance liquid chromatography, a sensitive method that can detect approximately 5% heteroplasmy. As a result, we detected a heteroplasmic mtDNA variation in 13 RM women (27%) and in 9 control women (19%). Seven synonymous and five non-synonymous changes were detected within coding regions. In addition, seven heteroplasmic variations were detected within the non-coding control region. We were also able to show the presence of the variations in eight placental samples from three heteroplasmic women. In three of these cases, the proportion of variant mtDNA was higher in the placenta compared with that in the mother. We conclude that our sensitive methodology revealed a higher frequency of samples with heteroplasmic variations than expected in women with both RM and controls. However, no apparent increased frequency of heteroplasmic mtDNA variations or amounts of aberrant mtDNA was detected in the RM group. In addition, none of the detected variations were previously known to be pathogenic and therefore they are an unlikely cause of miscarriage.


American Journal of Human Genetics | 2011

Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy

Alexandra Götz; Henna Tyynismaa; Liliya Euro; Pekka Ellonen; Tuulia Hyötyläinen; Tiina Ojala; Riikka H. Hämäläinen; Johanna Tommiska; Taneli Raivio; Matej Orešič; Riitta Karikoski; Outi Tammela; Kalle O. J. Simola; Anders Paetau; Tiina Tyni; Anu Suomalainen


Human Molecular Genetics | 2012

Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy

Jenni M. Elo; Srujana S. Yadavalli; Liliya Euro; Pirjo Isohanni; Alexandra Götz; Christopher J. Carroll; Leena Valanne; Fowzan S. Alkuraya; Johanna Uusimaa; Anders Paetau; Eric M. Caruso; Helena Pihko; Michael Ibba; Henna Tyynismaa; Anu Suomalainen


Cardiogenetics | 2013

Atrial fibrillation is poorly tolerated by patients with hypertrophic concentric cardiomyopathy caused by mitochondrial tRNALeu (UUR) mutations

Tiina Heliö; Alexandra Götz; Janne Rapola; Sari Kiuru-Enari; Sari Kivistö; Terttu Heikinheimo; Anu Suomalainen


Archive | 2012

The molecular background of severe mitochondrial respiratory chain deficiencies in children and adults, with special emphasis on mitochondrial cardiomyopathies.

Alexandra Götz

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Helena Pihko

Helsinki University Central Hospital

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Liliya Euro

University of Helsinki

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