Mitochondria in biology and medicine – 2023

Mitochondrion, Journal Year: 2024, Volume and Issue: 76, P. 101853 - 101853

Published: Feb. 28, 2024

Language: Английский

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Mitochondrial Ataxias: Molecular Classification and Clinical Heterogeneity

Neurology International, Journal Year: 2022, Volume and Issue: 14(2), P. 337 - 356

Published: April 2, 2022

Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, spinal peripheral lesions leading to proprioceptive loss. Despite ataxias having no specific defining features, they should included hereditary differential diagnosis, given high prevalence PMDs. This review focuses on clinical neuropathological features genetic background PMDs which ataxia prominent manifestation.

Language: Английский

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Genetic testing for non-parkinsonian movement disorders: Navigating the diagnostic maze

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 121, P. 106033 - 106033

Published: Feb. 17, 2024

Genetic testing has become a valuable diagnostic tool for movement disorders due to substantial advancements in understanding their genetic basis. However, the heterogeneity of poses significant challenge, with many genes implicated different subtypes. This paper aims provide neurologist's perspective on approaching patients hereditary hyperkinetic focus select forms dystonia, paroxysmal dyskinesia, chorea, and ataxia. Age at onset, initial symptoms, severity, as well presence any concurrent neurological non-neurological features, contribute individual clinical profiles non-parkinsonian disorders, aiding selection appropriate strategies. There are also more specific clues that may facilitate decision-making process be highly certain conditions, such diurnal fluctuations l-dopa response dopa-responsive triggering factors, duration frequency attacks dyskinesia. While mutational spectrum across is broad, groups diseases tend associated types pathogenic variants, repeat expansions ataxias. Some these variants cannot detected by standard methods, panel or exome sequencing, but require investigation intronic regions expansions, Friedreich's FGF14-linked With our advancing knowledge underpinnings incorporation precise personalized strategies can enhance patient care, prognosis, application development targeted therapeutic interventions.

Language: Английский

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Mitochondrial encephalomyopathy

Handbook of clinical neurology, Journal Year: 2023, Volume and Issue: unknown, P. 563 - 585

Published: Jan. 1, 2023

Language: Английский

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Dystonia and mitochondrial disease: the movement disorder connection revisited in 900 genetically diagnosed patients

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(7), P. 4685 - 4692

Published: May 22, 2024

Language: Английский

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Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis

Movement Disorders Clinical Practice, Journal Year: 2024, Volume and Issue: 11(8), P. 948 - 965

Published: June 28, 2024

Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence 1 in 4300. They can result from mutations either nuclear DNA (nDNA) or (mtDNA). These disorders multisystemic and mainly affect high energy-demanding tissues, such as muscle central nervous system (CNS). Among many clinical features CNS involvement, parkinsonism is one movement PMDs.

Language: Английский

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Mitochondrial ataxia - Unravelling the puzzle

Annals of Movement Disorders, Journal Year: 2024, Volume and Issue: 7(2), P. 78 - 87

Published: May 1, 2024

Abstract Primary mitochondrial diseases (PMDs) can be caused by a defect in any of the metabolic pathways, due to or nuclear DNA mutations, occurring de novo. Ataxia is one most common presentations disorders and may present as pure cerebellar, sensory mixed ataxia. Understanding basic physiological mechanisms, classification ataxias, phenotypic heterogeneity, respective diagnostic evaluation methods paramount recognize this disorder. We conducted comprehensive literature search using PubMed database before July 1, 2024, synthesize narrative review, focusing on various aspects primary disorders, particularly those associated with

Language: Английский

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Complex neurological and multisystem presentations in mitochondrial disease

Handbook of clinical neurology, Journal Year: 2023, Volume and Issue: unknown, P. 117 - 124

Published: Jan. 1, 2023

Language: Английский

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Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine

Movement Disorders, Journal Year: 2023, Volume and Issue: 39(1), P. 29 - 35

Published: Nov. 14, 2023

Four decades of research highlighted a significant role for mitochondrial dysfunction in the pathogenesis movement disorders. A first milestone was set by discovery that neurotoxin N-methyl-4-phenylpyridinium (MPP+), an apoptosis-inducing complex I inhibitor, induces parkinsonism selectively damaging substantia nigra.1, 2 This report sparked intensive investigations on mitochondria Parkinson's disease (PD),3 fueled recognition functions several PD-associated genes.2 Sequencing genome completed 1981.4 Reports linking DNA (mtDNA) variants to neurological phenotypes rapidly followed. Notably, two early works identified dystonia as prominent feature distinct syndromes,5, 6 leading speculation "movement disorders might have etiology".7 The association between diseases and various has been confirmed case reports few larger series.8-11 Nonetheless, systematic explorations underlying pathophysiological mechanisms are scarce. Recently, independent studies elucidated direct causal relationship isolated genes encoding components ATP synthase (ATPase).12, 13 These remarkable findings encouraged us reappraise "mitochondria-movement disorder connection"7 from genetics-driven perspective. We posit mild energetic failure caused specific ATPase may influence synaptic activity nodes motor circuits involved pathogenesis. modulation driven other genetic or environmental stressors play functional network alterations seen more common idiopathic dystonias. Unique among cellular organelles, underlie dual genomic control both autochthonous mtDNA nuclear genome.14, 15 MtDNA encodes subunits enzymatic complexes governing oxidative phosphorylation (OXPHOS) 24 RNAs.4 Further >1000 proteins nuclear-encoded.16 They not only directly OXPHOS, but also respiratory chain-complex assembly, replication, expression, repair, well metabolic pathways.15 Defects any these processes result phenotype. Dystonia is recurrently observed manifestation diseases, particularly pediatric cohorts.8-11, 17 In this setting, usually occurs within multisystemic such Leigh syndrome, progressive encephalopathy associated with basal-ganglia necrotizing lesions.18 syndrome presents childhood, triggered infection illnesses after initial period normal development.19 Following crises, affected children develop symptoms including developmental regression, ataxia, dystonia. Variants (eg, PMPCA) present wide clinical spectrum ranging relatively dystonic severe epileptic encephalopathies disorders.20 Additionally, key rare syndromes Mohr-Tranebjaerg disease, along deafness optic atrophy.6 Neurodegenerative background part their cases, can precede manifestations years21 outlast further typical signs.22 Together, variety defects linked dysfunction, therefore, representing rather non-specific manifestation, fitting older definition "secondary" broader Isolated presentation exceptional.21 OXPHOS orchestrated five multiprotein located inner membrane. four (I–IV), known chain, generate transmembrane proton gradient transferring electrons molecular oxygen.23 fifth complex, referred ATPase, funnels chemical force production ATP.24 consists globular F1 head made three αβ dimers membrane-embedded Fo subcomplex formed pore ring multiple c subunits.25, 26 moieties connected peripheral stalk central stalk. peculiar structure enables synthesis via "chemomechanical" coupling.27 Indeed, influx through drives rotation c-ring, which transmitted catalytic sector, where reaction ADP + Pi → occurs.28 Dimeric assembly at membrane modular fashion contributing shaping cristae.29 Only coded (MT-ATP6 MT-ATP8),30 whereas remaining ones nuclear-encoded.31 underrepresented etiologies.31 Beyond possible epidemiological considerations, issue be historically related earlier difficulties assaying V activity.32, 33 group Anita Harding 1990 reported human describing MT-ATP6 variant encompassing delay, dementia, neuropathy.34 disease-causing gene ATP5F1E, 20 years later.35 Most ATPase-deficiency clinically expected cardinal enzyme. syndrome.36 Early-onset main biallelic (ATP5F1A, ATP5F1D, ATP5MK).37-40 settings, dystonia41 noticed stabilization crises. An ATPase-related phenotype time heterozygous ATP5MC3, codes c-subunit.42 Neilson colleagues42 described missense (p.Asn106Lys) autosomal dominant pedigree relatives displayed either childhood-onset generalized adult-onset spastic paraplegia. Several members focal limb neck same p.Asn106Lys found de novo event nonrelated 11-year-old boy suffering upper-limb dystonia.42 report, observations expanded Zech et al13 ATP5MC3 15-year-old girl delay ATP5F1E homozygous patients who developed limb/generalized Furthermore, they inheritance pattern ATP5F1A, α-subunit subcomplex.13 Biallelic ATP5F1A were previously infants fatal neonatal encephalopathy.13 non-related cerebral-palsy third proband failure-to-thrive lactic acidosis months life, subsequently recovered had no persistent neurologic Finally, individuated ATP5PO, subunit OSCP, new dystonia.13 latest families ATP5F1B, coding β-subunit sector. individuals, age onset ranged infancy adolescence. began showed different rate progression, all individuals retained gait additional features.12 Non-affected carried ATP5F1B variant, pointing reduced penetrance mechanism. Intriguingly, single previous report. Here, affecting nearby amino acid cause congenital uncoupling syndrome.43 Table 1 summarizes drive pathogenicity variants.44 constant biochemical reduction activity, whose extent correlate phenotypic severity.13, 42 variants, protein levels invariably reduced.37, 38, 40 finding accompanied cristae morphology.37, Conversely, gross morphology mostly preserved disorders.12, alter highly conserved acids interhelical intersubunit contact areas proteins, suggesting negative effect mutant subunits. Interestingly, ATP5F1B-related dystonia, even slightly increased assemble oligomeric structures.12 phenomenon reflect attempt compensation, because dimerization oligomerization regulate efficiency.45 display high predicted constraints against loss-of-function (see 1). Therefore, it cannot ruled out haploinsufficiency pathogenic mechanism some defect-related disorders, although evidence currently lacking. Subunits copies functioning ATPase. relative expression mutated likely contributes variable incomplete milder phenotypes. Differential homologues turn shaped factors. Oxygen consumption variably recessive phenotypes,13 dystonia.12 opposite alteration, namely increase oxygen hallmark allelic ATP5F1B-associated consequence dissipation without parallel generation defective ATPase.43 Genetic, imaging, studies46, 47 involvement pathways pathophysiology biological eventually converge basal ganglia dopaminergic neurotransmission. striatal lesions.19 obvious structural damage is, however, missing net consequences quite differ those chain (for overview see Goldstein al Zeviani Viscomi).32, 48 cells, I–IV impair production, reactive species (ROS) formation, induce cell death. selective inhibition results depletion, enhanced ROS apoptosis.49 less efficient energy supply produce relevant disturbance susceptible networks. Among monoaminergic systems, peculiarity neurons resides intrinsic cytotoxicity dopamine, its metabolism monoamine oxidase ROS.50, 51 Graves al51 terminals, radicals produced do stress, shuttled entering IV electron donor contribute Fig. application inhibitor oligomycin dropping dopamine release. recycling system one hand limit autoxidation needed phasic firing neurons.51, 52 tenuous balance easily disrupted if efficiency decreases). hypothesis tested experimentally expressing setting 1) exploring link murine model). semicritical deficit manifest model dopa-responsive upregulated striatum, F1-rotor ATP5F1C.53 could represent compensatory biogenesis inefficient firing. From perspective, widespread changes neuronal (striatal, cortical, cerebellar) dystonia.46, fluctuations lead abnormal plasticity aberrant mechanisms, animal models.46, impairment explain lacking response levodopa therapy It furthermore highlights unmet need overarching therapeutic target modulatory dystonia-relevant circuits. classical forms monogenic penetrance. Affected subjects become symptomatic asymptomatic carriers convert beyond decade TOR1A-related dystonia).54 peculiarities suggest extragenetic According second-hit hypothesis, "first" alteration underlies maladaptive requires factors manifest.55 Alternatively, compensation endogenous protection role.55 interplay genetics especially detrimental defined time-window neurodevelopment. age-dependent susceptibility paraplegia childhood- vs. ATP5MC3-related disease). recapitulates suggests modifiers shape otherwise potentially compensated defects. respect interesting explore presence endophenotype carriers.56 Two clusters emerging. Recessive non-progressive becomes evident crises worsening encephalopathy. Some pedigrees makes clear slight disturbances entail alterations. early-onset surprising. pictures, detection poor.57 much number featuring warranting reverse phenotyping diagnosed cases. Monogenic offer unique insights into phenotypically sporadic conditions. history neurogenetics PD exemplifies notion. α-synuclein familial PD58 preceded identification Lewy bodies,59 thereafter, contributed etiological substrate PD. Such strong paradigm recent delineation dystonias reawakes our endeavor fulfill goal. exceptional certain exquisite vulnerability circuitries cofactors. Dissecting basis may, help shed light (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: Design, Execution, Review Critique; (3) Manuscript: Writing First Draft, Critique. E.I. 1A, 3A S.B. 3B N.E.M. D.G. H.P. J.W. M.Z. 3A, authors financial disclosures. supported European Joint Programme Rare Diseases (EJP-RD WP17 mobility fellowship). receive support German Foundation (DFG 458949627; WI 1820/14-1; ZE 1213/2-1). acknowledges grant Federal Ministry Education (BMBF, Bonn, Germany) awarded Network Mitochondrial Disorders (mitoNET, 01GM1906A). (EJP RD Transnational Call 2022), Germany), project PreDYT (Predictive biomarkers 01GM2302), (BMBF) Free State Bavaria under Excellence Strategy Government Länder, Technical University Munich-Institute Advanced Study. Italian Health Fondazione Mariani. Open Access funding enabled organized Projekt DEAL. Not applicable.

Language: Английский

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Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16746 - 16746

Published: Nov. 25, 2023

Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment the oxidative phosphorylation (OXPHOS). The unique features genetics and pivotal role mitochondria in cell biology explain phenotypical heterogeneity primary resulting diagnostic challenges that follow. Some peculiar ("red flags") may indicate a disease, helping physician to orient this maze. In narrative review, we aimed outline most common red flags offering general overview on topic could help physicians untangle medicine complexity.

Language: Английский

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