Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalo-cardiomyopathies. Since ATP synthase subunits are encoded by both mitochondrial and nuclear DNA, pathogenic variants can be found in either genome. In addition, the biogenesis of ATP synthase requires several assembly factors, some of which are also hotspots for pathogenic variants. While variants of MT-ATP6 and TMEM70 represent the most common cases of mitochondrial and nuclear DNA mutations respectively, the advent of next-generation sequencing has revealed new pathogenic variants in a number of structural genes and TMEM70, sometimes with truly peculiar genetics. Here we present a systematic review of the reported cases and discuss biochemical mechanisms, through which they are affecting ATP synthase. We explore how the knowledge of pathophysiology can improve our understanding of enzyme biogenesis and function. Keywords: Mitochondrial diseases o ATP synthase o Nuclear DNA o Mitochondrial DNA o TMEM70.

• MeSH
• fenotyp * MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mitochondriální DNA genetika   MeSH
• mitochondriální nemoci genetika   enzymologie   MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondriální protonové ATPasy * genetika   metabolismus   MeSH
• mitochondrie enzymologie   genetika   MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• membránové proteiny MeSH
• mitochondriální DNA MeSH
• mitochondriální proteiny MeSH
• mitochondriální protonové ATPasy * MeSH
• TMEM70 protein, human MeSH Prohlížeč

Life manifests as growth, movement or heat production that occurs thanks to the energy accepted from the outside environment. The basis of energy transduction attracted the Czech researchers since the beginning of the 20th century. It further accelerated after World War II, when the new Institute of Physiology was established in 1954. When it was found that energy is stored in the form of adenosine triphosphate (ATP) that can be used by numerous reactions as energy source and is produced in the process called oxidative phosphorylation localized in mitochondria, the investigation focused on this cellular organelle. Although the Czech scientists had to overcome various obstacles including Communist party leadership, driven by curiosity, boldness, and enthusiasm, they characterized broad spectrum of mitochondrial properties in different tissues in (patho)physiological conditions in collaboration with many world-known laboratories. The current review summarizes the contribution of the Czech scientists to the bioenergetic and mitochondrial research in the global context. Keywords: Mitochondria, Bioenergetics, Chemiosmotic coupling.

• MeSH
• biomedicínský výzkum dějiny   trendy   MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• energetický metabolismus * MeSH
• lidé MeSH
• mitochondrie * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. RESULTS: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3-4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. CONCLUSION: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.

• Klíčová slova
• ATAD3A, Mitochondria, OXPHOS, Pontocerebellar hypoplasia,
• MeSH
• ATPázy spojené s různými buněčnými aktivitami * genetika   MeSH
• biologická variabilita populace * MeSH
• fenotyp MeSH
• lidé MeSH
• mitochondrie * genetika   MeSH
• nemoci mozečku MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATAD3A protein, human MeSH Prohlížeč
• ATPázy spojené s různými buněčnými aktivitami * MeSH

In this study, we report on a novel heteroplasmic pathogenic variant in mitochondrial DNA (mtDNA). The studied patient had myoclonus, epilepsy, muscle weakness, and hearing impairment and harbored a heteroplasmic m.8315A>C variant in the MTTK gene with a mutation load ranging from 71% to >96% in tested tissues. In muscle mitochondria, markedly decreased activities of respiratory chain complex I + III and complex IV were observed together with mildly reduced amounts of complex I and complex V (with the detection of V*- and free F1-subcomplexes) and a diminished level of complex IV holoenzyme. This pattern was previously seen in other MTTK pathogenic variants. The novel variant was not present in internal and publicly available control databases. Our report further expands the spectrum of MTTK variants associated with mitochondrial encephalopathies in adults.

• Klíčová slova
• MTTK gene, OXPHOS, heteroplasmy, m.8315A>C, mtDNA,
• MeSH
• dospělí MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• mitochondriální encefalomyopatie * patologie   MeSH
• respirační komplex IV MeSH
• svalové mitochondrie metabolismus   MeSH
• syndrom MERRF * genetika   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální DNA MeSH
• respirační komplex IV MeSH

BACKGROUND: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. METHODS: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. RESULTS: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. CONCLUSIONS: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.

• Klíčová slova
• Complex I, Leigh syndrome, MEGS, MELAS syndrome, MT-ND genes, Mitochondria, mtDNA,
• MeSH
• biopsie MeSH
• dítě MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• kojenec MeSH
• kosterní svaly metabolismus   MeSH
• kultivované buňky MeSH
• Leighova nemoc genetika   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mitochondriální DNA * MeSH
• mitochondriální nemoci genetika   MeSH
• mladiství MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• mutace * MeSH
• novorozenec MeSH
• respirační komplex I nedostatek   genetika   metabolismus   MeSH
• syndrom MELAS genetika   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mitochondriální DNA * MeSH
• respirační komplex I MeSH

Common inbred strains of the laboratory rat can be divided into four different mitochondrial DNA haplotype groups represented by the SHR, BN, LEW, and F344 strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. LEW mitochondrial genomes by comparing the SHR to a new SHR conplastic strain, SHR-mt(LEW); these strains are genetically identical except for their mitochondrial genomes. Complete mitochondrial DNA (mtDNA) sequence analysis comparing the SHR and LEW strains revealed gene variants encoding amino acid substitutions limited to a single mitochondrial enzyme complex, NADH dehydrogenase (complex I), affecting subunits 2, 4, and 5. Two of the variants in the mt-Nd4 subunit gene are located close to variants known to be associated with exercise intolerance and diabetes mellitus in humans. No variants were found in tRNA or rRNA genes. These variants in mt-Nd2, mt-Nd4, and mt-Nd5 in the SHR-mt(LEW) conplastic strain were linked to reductions in oxidative and nonoxidative glucose metabolism in skeletal muscle. In addition, SHR-mt(LEW) conplastic rats showed increased serum nonesterified fatty acid levels and resistance to insulin stimulated incorporation of glucose into adipose tissue lipids. These results provide evidence that inherited variation in mitochondrial genes encoding respiratory chain complex I subunits, in the absence of variation in the nuclear genome and other confounding factors, can influence glucose and lipid metabolism when expressed on the nuclear genetic background of the SHR strain.

• MeSH
• adeninnukleotidy metabolismus   MeSH
• dědičnost MeSH
• dietní sacharidy aplikace a dávkování   metabolismus   MeSH
• fenotyp MeSH
• fruktosa aplikace a dávkování   metabolismus   MeSH
• genetická variace * MeSH
• haplotypy MeSH
• hypertenze krev   enzymologie   genetika   patofyziologie   MeSH
• inzulin krev   MeSH
• inzulinová rezistence genetika   MeSH
• kosterní svaly enzymologie   MeSH
• krevní glukóza metabolismus   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• kyseliny mastné neesterifikované krev   MeSH
• mitochondriální DNA genetika   MeSH
• modely nemocí na zvířatech MeSH
• molekulární sekvence - údaje MeSH
• NADH-dehydrogenasa genetika   metabolismus   MeSH
• oxidativní fosforylace * MeSH
• potkani inbrední BN MeSH
• potkani inbrední F344 MeSH
• potkani inbrední LEW MeSH
• potkani inbrední SHR MeSH
• sekvence aminokyselin MeSH
• srdeční frekvence MeSH
• tuková tkáň enzymologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adeninnukleotidy MeSH
• dietní sacharidy MeSH
• fruktosa MeSH
• inzulin MeSH
• krevní glukóza MeSH
• kyseliny mastné neesterifikované MeSH
• mitochondriální DNA MeSH
• NADH dehydrogenase subunit 2, rat MeSH Prohlížeč
• NADH dehydrogenase subunit 4 MeSH Prohlížeč
• NADH dehydrogenase subunit 5, rat MeSH Prohlížeč
• NADH-dehydrogenasa MeSH

BACKGROUND: To strengthen research and differential diagnostics of mitochondrial disorders, we constructed and validated an oligonucleotide microarray (h-MitoArray) allowing expression analysis of 1632 human genes involved in mitochondrial biology, cell cycle regulation, signal transduction and apoptosis. Using h-MitoArray we analyzed gene expression profiles in 9 control and 13 fibroblast cell lines from patients with F1Fo ATP synthase deficiency consisting of 2 patients with mt9205deltaTA microdeletion and a genetically heterogeneous group of 11 patients with not yet characterized nuclear defects. Analysing gene expression profiles, we attempted to classify patients into expected defect specific subgroups, and subsequently reveal group specific compensatory changes, identify potential phenotype causing pathways and define candidate disease causing genes. RESULTS: Molecular studies, in combination with unsupervised clustering methods, defined three subgroups of patient cell lines--M group with mtDNA mutation and N1 and N2 groups with nuclear defect. Comparison of expression profiles and functional annotation, gene enrichment and pathway analyses of differentially expressed genes revealed in the M group a transcription profile suggestive of synchronized suppression of mitochondrial biogenesis and G1/S arrest. The N1 group showed elevated expression of complex I and reduced expression of complexes III, V, and V-type ATP synthase subunit genes, reduced expression of genes involved in phosphorylation dependent signaling along MAPK, Jak-STAT, JNK, and p38 MAP kinase pathways, signs of activated apoptosis and oxidative stress resembling phenotype of premature senescent fibroblasts. No specific functionally meaningful changes, except of signs of activated apoptosis, were detected in the N2 group. Evaluation of individual gene expression profiles confirmed already known ATP6/ATP8 defect in patients from the M group and indicated several candidate disease causing genes for nuclear defects. CONCLUSION: Our analysis showed that deficiency in the ATP synthase protein complex amount is generally accompanied by only minor changes in expression of ATP synthase related genes. It also suggested that the site (mtDNA vs nuclear DNA) and the severity (ATP synthase content) of the underlying defect have diverse effects on cellular gene expression phenotypes, which warrants further investigation of cell cycle regulatory and signal transduction pathways in other OXPHOS disorders and related pharmacological models.

• MeSH
• analýza hlavních komponent MeSH
• buněčné linie MeSH
• fenotyp MeSH
• fibroblasty enzymologie   MeSH
• genom mitochondriální MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• mitochondriální nemoci klasifikace   diagnóza   enzymologie   genetika   MeSH
• mitochondriální protonové ATPasy nedostatek   genetika   MeSH
• modely genetické MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů metody   statistika a číselné údaje   MeSH
• sekvenční delece MeSH
• shluková analýza MeSH
• stanovení celkové genové exprese metody   statistika a číselné údaje   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• validační studie MeSH
• Názvy látek
• F1F0-ATP synthase MeSH Prohlížeč
• mitochondriální DNA MeSH
• mitochondriální protonové ATPasy MeSH

Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.

• MeSH
• diabetes mellitus 2. typu genetika   MeSH
• genetická variace * MeSH
• genom * MeSH
• genová dávka MeSH
• haplotypy MeSH
• krysa rodu Rattus MeSH
• mitochondriální DNA genetika   MeSH
• mitochondrie enzymologie   genetika   MeSH
• polymorfismus genetický MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• respirační komplex IV genetika   MeSH
• rizikové faktory MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• substituce aminokyselin MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• mitochondriální DNA MeSH
• respirační komplex IV MeSH