TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome

Spiegel, Ronen; Khayat, Morad; Shalev, Stavit A.; Horovitz, Yoseph; Mandel, Hanna; Hershkovitz, Eli; Barghuti, Flora; Shaag, Avraham; Saada, Ann; Korman, Stanley H.; Elpeleg, Orly; Yatsiv, Ido

doi:10.1136/jmg.2010.084608

Cited by 63 publications

(46 citation statements)

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“…Pathogenic mutations to MTATP6 [92] can result in maternally inherited Leigh syndrome (MILS) [93] and neuropathy, ataxia, retinal pigmentosa (NARP) [90,92]. Additionally, mutations to CV assembly factors, TMEM70 [94] and ATPAF2 [95] have been identified and present with cardiomyopathy, hypotonia, intrauterine growth restriction and oligohydramnios [94,95] (Table 1).…”

Section: Oxphos Complex Vmentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Section: Oxphos Complex Vmentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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“…One individual with Type IV 3-methylglutaconic aciduria, had mild symptoms, but persistent hypertrophic cardiomyopathy was a feature [70]. In a second study, six new patients were identified with infantile onset cataracts, early gastrointestinal dysfunction, and congenital hypertonia with contractures resembling distal arthrogryposis [71].…”

Section: Mutations In Tmem70 and Complex V Deficiencymentioning

confidence: 98%

Nuclear Genes Causing Mitochondrial Cardiomyopathy

Ware

Towbin

2012

Mitochondrial Disorders Caused by Nuclear Genes

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The heart functions to pump blood throughout the body and is capable of adjusting the frequency and intensity of its repetitive contractions to meet energetic demands. Cardiac myocytes are connected in series and, unlike skeletal muscle fibers, do not assemble in parallel arrays but bifurcate and join to form a three-dimensional network [1][2][3][4]. Mitochondria occupy greater than 30 % of cardiomyocyte volume and are organized in densely packed rows under the sarcolemma and between myofilaments. This ordered arrangement ensures that a constant diffusion distance exists between mitochondria and the core of the myofilament. The myofibrils are formed by repeating sarcomere units. The sarcomeres are the basic contractile units and are composed of thin filaments consisting of cardiac actin, alpha tropomyosin, and troponins T, I, and C and thick filaments composed of myosin heavy chain, myosin light chains, and myosin-binding proteins C, H, and X. Myosin heavy chain contains the ATPase activity that drives cardiac contraction.The heart is one of the major energy-consuming organs. Energy is primarily stored in the form of ATP or phosphocreatine, which is formed by creatine kinasemediated phosphorylation of creatine by ATP. Overall, the heart uses approximately 1 mM ATP per second and requires complete energy substrate renewal about every 20 seconds. [5]. The heart is promiscuous in its utilization of energy substrates and can use fatty acids, carbohydrates, lactate, ketone bodies, or amino acids. Prenatally, energy is primarily derived from glucose as the substrate undergoing glycolysis. At the time of birth, the myocardium switches from anaerobic glycolysis to fatty acid oxidation and oxidative phosphorylation as a means of ATP production [6,7]. Fatty acids remain the preferred substrate throughout postnatal life. Mouse models have demonstrated that there is a strong activation of mitochondrial biogenesis in

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“…[6,7]. У всех пациентов выявляются выраженный лактат-ацидоз, гипераммониемия, во время кризов -гипераланиниемия и 3-метилглютаконовая ацидурия [4,5].…”

Section: клиническая картинаunclassified

“…2) в гетерози-готном состоянии, приводящая к сдвигу рамки считыва-ния p.Thr193Serfs*6. Мутации описаны ранее у пациен-тов с недостаточностью АТФ-синтетазы и неонатальной митохондриальной энцефалокардиомиопатией [4,6]. Обе мутации, выявленные методом массового парал-лельного секвенирования, подтверждены методом пря-мого автоматического секвенирования по Сэнгеру.…”

Section: клинический случайunclassified

“…Нарушение синтеза АТФ приводит к повреждению митохондрий, нарушению функций клеток, в том числе в миокарде, и возникно-вению сердечной недостаточности [2]. Недостаточность АТФ-синтазы, обусловленная мутациями в гене TMEM70 (OMIM 612418), -редкое наследственное заболевание, возникающее в результате нарушения работы дыхатель-ной цепи митохондрий [3][4][5]. Ген TMEM70, длиной 10 347 пар нуклеотидов, расположенный в хромосомной обла-сти 8q21.11, кодирует митохондриальный трансмем-бранный белок TMEM70, длиной 260 аминокислотных остатков, молекулярной массой 28 969 Да, играющий важную роль в биогенезе митохондриальной АТФазы.…”

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Mitochondrial Complex V (ATP-synthase) Deficiency Nuclear Type 2, Caused by Mutation in the TMEM70 Gene: the First Case in Russia

Журкова¹,

Вашакмадзе²,

Савостьянов³

et al. 2018

Pediatr. farmakol.

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Mitochondrial respiratory chain complex V deficiency, type 2 is a rare hereditary disease developing due to mutations in TMEM70 Недостаточность комплекса V дыхательной цепи митохондрий, тип 2, обусловленная мутациями в ядерном гено-ме -редкое наследственное заболевание, возникающее вследствие мутаций в гене TMEM70 (трансмембранного протеина 70). С использованием технологии массового параллельного секвенирования у пациента с особенно-стями фенотипа, синдромом некомпактного миокарда левого желудочка и врожденным пороком сердца впервые в России в гене

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TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome

Abstract: The current report corroborates the previously described unique phenotype of TMEM70 deficiency. The study identifies TMEM70 gene defect as a pan-ethnic disorder and further redefines it as the most common cause of nuclear-origin ATP synthase deficiency.

Cited by 63 publications

References 20 publications

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Nuclear Genes Causing Mitochondrial Cardiomyopathy

Mitochondrial Complex V (ATP-synthase) Deficiency Nuclear Type 2, Caused by Mutation in the TMEM70 Gene: the First Case in Russia

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