Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

Komulainen, Tuomas; Hautakangas, Milla‐Riikka; Hinttala, Reetta; Pakanen, Salla; Vähäsarja, Vesa; Lehenkari, Petri; Olsén, Päivi; Vieira, Päivi; Saarenpää‐Heikkilä, Outi; Palmio, Johanna; Tuominen, Hannu; Kinnunen, Pentti; Majamaa, Kari; Rantala, Heikki; Uusimaa, Johanna

doi:10.1007/8904_2015_438

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…A final potential explanation for the regional differences in mtDNA methylation and coverage could be copy number changes within the mtDNA molecule. Rare cases have been reported of mtDNA deletions and rearrangements in patients with mitochondrial disease [48] and neuromuscular disease [49]. The regional pattern of methylation in mtDNA that we observed was similar between normal and disease tissues which could support the conclusion that the patterns are not caused by (pathology-associated) copy number changes.…”

Section: Discussionsupporting

confidence: 85%

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation

et al. 2018

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BackgroundAltered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). Mitochondria have multiple copies of a 16 kb circular genome that contains genes that are vital for their function. While DNA methylation is known to alter the nuclear genome in CRC, it is not clear whether it could have a similar influence in mtDNA; indeed, currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. Thus our goal here was to determine whether the methylation state of mtDNA is linked to mitochondrial gene transcription in colorectal adenomas, and to assess its suitability as a biomarker in CRC.MethodsTo investigate the relationship between DNA methylation and mitochondrial transcripts in adenomas, we performed RNA-sequencing and Whole Genome Bisulphite Sequencing (WGBS) of mtDNA-enriched DNA from normal mucosa and paired adenoma patient samples.ResultsTranscriptional profiling indicated that adenomas had reduced mitochondrial proton transport versus normal mucosa, consistent with altered mitochondrial function. The expression of 3 tRNAs that are transcribed from mtDNA were also decreased in adenoma. Overall methylation of CG dinucleotides in the nuclear genome was reduced in adenomas (68%) compared to normal mucosa (75%, P < 0.01). Methylation in mtDNA was low (1%) in both normal and adenoma tissue but we observed clusters of higher methylation at the ribosomal RNA genes. Levels of methylation within these regions did not differ between normal and adenoma tissue.ConclusionsWe provide evidence that low-level methylation of specific sites does exist in the mitochondrial genome but that it is not associated with mitochondrial gene transcription changes in adenomas. Furthermore, as no large scale changes to mtDNA methylation were observed it is unlikely to be a suitable biomarker for early-stage CRC.Electronic supplementary materialThe online version of this article (10.1186/s40364-018-0151-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation

et al. 2018

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“…As these changes can be induced by physiological processes, such as nutrient stress, it is common to see different mitochondrial morphologies in a healthy cell ( Giacomello et al, 2020 ). However, important deviations have been found in cells with mitochondrial diseases ( Liu et al, 2012 ; Komulainen et al, 2015 ; Vincent et al, 2016 ; Felczak et al, 2017 ; Molnar and Kovacs, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Hernández-Ainsa

López‐Gallardo

García-Jiménez

et al. 2022

Disease Models &Amp; Mechanisms

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Pearson syndrome (PS) is a rare multisystem disease caused by single large scale mitochondrial DNA deletions (SLSMDs). PS presents early in infancy and it is mainly characterized by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus development of new models for the study of PS and new therapy strategies is essential. In this work we report three different cell models carrying a SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSC). All studied models exhibited an aberrant mitochondrial ultrastructure and defective OXPHOS function, showing a decrease in different parameters such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite that, iPSC harbouring “common deletion” were able to differentiate into three germ layers. Besides, cybrids clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile, therefore we consider these three models are useful for the in vitro study of the PS as well as for testing new specific therapies.

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“…Mitochondrial genome stability may be disturbed by mutations in nuclear genes encoding mostly proteins that are part of the mitoproteome. Mitochondrial DNA replication depends on proteins such as POLG ( POLG ) and POLG2 ( POLG2 ) subunits of polymerase γ—the only replicative mitochondrial DNA polymerase, mitochondrial helicase TWINKLE ( TWNK also known as C10orf2 or PEO1 ), mitochondrial transcription factor A ( TFAM ), or RNase H1 ( RNASEH1 ) [ 3 , 4 ]. Besides this, for example conserved helicase/nuclease DNA2 ( DNA2 ) and mitochondrial genome maintenance exonuclease ( MGME1 ) influence mtDNA repair processes.…”

Section: Introductionmentioning

confidence: 99%

“…dNTP pool maintenance is supported, among others, by mitochondrial ADP/ATP translocase ANT1 ( SLC25A4 ), thymidine phosphorylase ( TYMP ), thymidine kinase ( TK2 ), deoxyguanosine kinase ( DGUOK ), ribonucleotide reductase (e.g., RRM2B ), succinyl-CoA synthetase (e.g., SUCLA2 ), and 4-aminobutyrate aminotransferase ( ABAT ). In addition to this, mitochondrial DNA dynamics is regulated by OPA1 ( OPA1 ) and MFN2 ( MFN2 ), mitochondrial inner membrane protein MPV17 ( MPV17 ) and F-box and leucine rich repeat protein 4 ( FBXL4 ) [ 4 ]. All these processes are involved in the pathophysiology of mitochondrial disorders because impaired mtDNA maintenance leads to the dysfunction of respiratory chain complexes and energy production [ 3 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Progressive External Ophthalmoplegia in Polish Patients—From Clinical Evaluation to Genetic Confirmation

Kierdaszuk

Kaliszewska

Rusecka

et al. 2020

Genes

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Mitochondrial encephalomyopathies comprise a group of heterogeneous disorders resulting from impaired oxidative phosphorylation (OxPhos). Among a variety of symptoms progressive external ophthalmoplegia (PEO) seems to be the most common. The aim of this study is to present clinical and genetic characteristics of Polish patients with PEO. Clinical, electrophysiological, neuroradiological, and morphological data of 84 patients were analyzed. Genetic studies of mitochondrial DNA (mtDNA) were performed in all patients. Among nuclear DNA (nDNA) genes POLG was sequenced in 41 patients, TWNK (C10orf2) in 13 patients, and RNASEH1 in 2 patients. Total of 27 patients were included in the chronic progressive external ophthalmoplegia (CPEO) group, 24 in the CPEO+ group. Twenty-six patients had mitochondrial encephalomyopathy (ME), six patients Kearns–Sayre syndrome (KSS), and one patient sensory ataxic neuropathy, dysarthria, ophthalmoparesis (SANDO) syndrome. Genetic analysis of nDNA genes revealed the presence of pathogenic or possibly pathogenic variants in the POLG gene in nine patients, the TWNK gene in five patients and the RNASEH1 gene in two patients. Detailed patients’ history and careful assessment of family history are essential in the diagnostic work-up. Genetic studies of both mtDNA and nDNA are necessary for the final diagnosis of progressive external ophthalmoplegia and for genetic counseling.

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Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

Cited by 10 publications

References 39 publications

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation

Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome

Progressive External Ophthalmoplegia in Polish Patients—From Clinical Evaluation to Genetic Confirmation

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