ATP Synthase Diseases of Mitochondrial Genetic Origin

Dautant, Alain; Meier, Thomas; Hahn, Alexander; Tribouillard-Tanvier, Déborah; Rago, Jean‐Paul di; Kucharczyk, Róża

doi:10.3389/fphys.2018.00329

Cited by 97 publications

(98 citation statements)

References 144 publications

(166 reference statements)

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“…Variants in ATP6 have long been recognized as a cause of mitochondrial disease. 1 Since the first description of a pathogenic m.8993 T > G variant in 1992, 1 more than 500 cases of ATP6-associated disease have been reported.…”

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confidence: 99%

Delineating MT-ATP6 -associated disease

et al. 2020

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ObjectiveTo delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations in a large international cohort.MethodsWe analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.ResultsWe identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic MT-ATP6 mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%–100%) and unaffected individuals (mean 73%, range 20%–100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).ConclusionsIn this currently largest series of patients with mitochondrial MT-ATP6 mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include MT-ATP6 mutations in the differential diagnosis of both ataxias and neuropathies.

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Delineating MT-ATP6 -associated disease

et al. 2020

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“…Several mutations affecting MT-ATP8 have already been described in patients presenting with heterogeneous clinical features, varying from neurological to cardiac disorders (12). Our patient harbored a variant in MT-ATP8 , which is likely to cause a deficit of ATP production.…”

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confidence: 99%

Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome

et al. 2018

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Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient.Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed.Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal.Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.

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“…mtDNA has high rates of mutation and sequence evolution, and mutant and wild-type mtDNA are present in the cell at different proportions [41,42]. The mtDNA mutations lead to abnormality in OXPHOS activity and ATP synthesis [43]. The mtDNA is exposed to OXPHOS-derived ROS without conventional histone proteins.…”

Section: Mitochondrial Genomementioning

confidence: 99%

Physiological Functions of Mitochondrial Reactive Oxygen Species

Choi¹,

Kim²

2020

Free Radical Medicine and Biology

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Mitochondria are the major energy producers within a cell in the form of adenosine triphosphate by oxidative phosphorylation. Normal mitochondrial metabolism inevitably generates reactive oxygen species (ROS), which have been considered to solely cause cellular damage. Increase of oxidative stress has been linked to various pathologies. Thus, mitochondrial ROS (mROS) were basically proposed as byproducts of oxidative metabolism, which undergo normalized by antioxidant enzymes. However, the mROS have extensively been esteemed to function as signalling molecules to regulate a wide variety of physiology. These phenomena are indeed dependent on mitochondrial redox status, which is dynamically altered under different physiological and pathological conditions. The oxidative stress is incurred by which the redox status is inclined to exceeded oxidation or reduction. Here, we attempt to integrate the recent advances in our understanding of the physiological functions of mROS.Keywords: mitochondrial ROS, oxidative stress, oxidative metabolism, redox signaling, mitochondrial physiology Free Radical Medicine and Biology 2 reactive metabolites of O 2 , including superoxide anion (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ), formed by one-and two-electron reductions of O 2 , respectively [7].In the presence of transition metal ions, the more reactive hydroxyl radical (OH · ) is formed. The O 2 ·− is rapidly dismutated to H 2 O 2 by two dismutases including Cu/ Zn-superoxide dismutase (Cu/ZnSOD) in mitochondrial intermembrane space and manganese-dependent superoxide dismutase (MnSOD) in mitochondrial matrix. Unless the dismutation of O 2 ·− is catalyzed into H 2 O 2 , the radical oxidant promotes DNA damage, protein oxidation and lipid peroxidation in many types of cells. H 2 O 2 is also cell damaging molecule to be degraded to water by catalase [8]. Although the O 2 ·− generation by respiratory complexes is a well-established phenomenon, it is still poorly understood in mechanism [9].Mitochondria have been implicated in the regulation of a number of physiological and pathological processes, including proliferation, differentiation, programmed cell death, innate immunity, autophagy, redox signalling, calcium homeostasis, hypoxic stress responses and stem cell reprogramming [10][11][12][13][14][15][16]. The mROS production contributes to mitochondrial damage in a range of pathologies, which is also is closely related to redox signalling in the cell [4,17]. However, accumulating evidences show that mROS are not only deleterious molecules derived from the cellular metabolism but also indispensable participants in diverse cellular signalling and regulations [18][19][20].In this chapter, we briefly summarize recent developments in our understanding of the involvement of mROS as signalling mediators in redox biology, rather than pathological stress, underlying physiological conditions.

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ATP Synthase Diseases of Mitochondrial Genetic Origin

Cited by 97 publications

References 144 publications

Delineating MT-ATP6 -associated disease

Delineating MT-ATP6 -associated disease

Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome

Physiological Functions of Mitochondrial Reactive Oxygen Species

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