An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases
Abstract
:1. Introduction
2. Overview of NMDs’ Clinical Features
3. Role of Mitochondria in Neuromuscular Diseases
4. Alteration of the Respiratory Chain Enzymes in NMDs
5. Alterations of Mitochondrial Enzymes Impair Neuromuscular Functions
Gene | Protein Name | Associated Neuromuscular Phenotypes | Pathogenic Mutations | Reference(s) |
---|---|---|---|---|
OPA1 | Optic atrophy 1 | Excercise intollerance, ataxia, and ophtalmoplegia | R455M (c.G1334A) S545R (c.C1635G) Q297X (c.C889T) A357T (c.G1069A) | [199,200] |
MFN2 | Mitofusin 2 | Type 2 Charcot–Marie–Tooth neuropathy, motor neuropathy, muscle weakness, and atrophy | R95W (c.C280T) R280H (c.G839A) | [202,203] |
ACO2 | Aconitase | Truncal hypotonia, muscle atrophy, and seizures | R607C (c.1819T9 P712l (c.C2135T) | [205] |
MDH2 | Malate dehydrogenase 2 | Muscle weakness, muscle atrophy, and severe hypotonia | P133L (c.C398T) P207L (c.C620T) G199Afs*10 (c596delG) | [206,207] |
CPTII | Carnitine palmitoyl transferase II | Severe infantile hepatocardiomuscular disease and myopathy | S113L (c.S113L) P227L (c.C1196T) K414TfsX7 (c.1238_1239delAG) K642Tfsx6 (c.1926_1935DEL) | [208,209,210] |
SCAD | Short-chain acylCoA dehydrogenase | Hypotonia, seizures, progressive myopathy, cardiomyopathy, and progressive external ophtalmoplegia | G209S (c.G625A) R171W (c.C511T) | [211] |
VLCAD | Very-long-chain acylCoA dehydrogenase | Early onset cardiac and skeletal myopathy | F418L (c.T1372C) G401A (c.G1322A) E454K (c.G1600A) R575Q (c.G1844A) | [211] |
ETFDH | Electron transfer flavoprotein dehydrogenase | Myopathy, dysphagia and respiratory failure, and multiple acyl-CoA dehydrogenase deficiency | A187V (c.C560T) D511N (c.G1531A) | [212,213] |
ECHS1 | Enoyl-CoA hydratase | Early onset Leigh-like syndrome, dystonia, and ataxia syndrome | A158D (c.C473A) Q159R (c.A476G) V82L (c.G244T) | [214] |
6. Alterations of Mitochondrial Carriers and NMDs
7. Diagnosis and Treatments
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Ach | acetylcholine |
ALS | amyotrophic lateral sclerosis |
ASOs | antisense oligonucleotides |
BCS1L | ubiquinol-cytochrome c reductase complex chaperone |
CMS | congenital myasthenic syndrome |
CMT | Charcot–Marie–Tooth disease |
DMPK | myotonic dystrophy protein kinase |
DOA | dominant optic atrophy FSHD, facioscapulohumeral muscular dystrophy |
HCMP | hypertrophic cardiomyopathy |
IBM | inclusion body myositis |
LS | Leigh syndrome |
MADD | multiple acyl-CoA dehydrogenase deficiency |
MD | muscular dystrophy |
MELAS | mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes |
MERRF | myoclonic epilepsy and ragged-red fibers |
MILS | maternally inherited Leigh syndrome |
NCLA | neonatal cardiomyopathy with lactic acidosis |
NMD | neuromuscular disease NMJ, neuromuscular junction |
PCH | pontocerebellar hypoplasia |
SCAD | short-chain acyl-CoA dehydrogenase |
SDH | succinate dehydrogenase |
SMN | survivor motor neuron |
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Gene/Protein | Function | Associated Neuromuscular Phenotype(s) | Pathogenic Mutant(s) | Reference(s) |
---|---|---|---|---|
Complex I Subunits | ||||
MTDN1 | H+ translocation | MELAS, dystonia, spasticity, and myopathy | T164A (m.A3796G) G131S (m.3697A) E214K (m.G3946A) Y215H (m.T3949C) | [86,87] |
MTDN3 | H+ translocation | Leigh syndrome | S34P (m.T10158C) | [88] |
MTDN4 | Putative proton channel | MELAS | T109A (m.A11084G) | [89] |
MTDN5 | Putative proton channel | MELAS | E145G (m.A12770G) M237L (m:A13045C) | [90] |
MTDN6 | H+ translocation | MELAS | A74V (m.G14453A) | [91] |
NDUFA1 | Assembly/stability | Leigh syndrome, hypotonia, nystagmus, and decreasedreflexes | G8R (c.G22C) R37S (c.G215C) | [92] |
NDUFA2 | Assembly/stability | Leigh syndrome, hypertrophic cardiomyopathy, and developmental delay | Exon 2 Skipping (c.G208A+5) | [93] |
NDUFA6 | Assembly/stability | Intrauterine growth retardation, respiratory insufficiency, and lactic acidosis | C115Y (c.G344A) | [82] |
NDUFA8 | Assembly/stability | Severe neonatal hypotonia, dysmorphic features, and epilepsy | E190K (c.G325A) A224V (c.C671T) | [84] |
NDUFA10 | Assembly/stability | Leigh syndrome and delayed psychomotor development | M1? (c.A1G) Q42R (c.A425G) | [94] |
NDUFA11 | Assembly/stability | Hypertrophic cardiomyopathy and no motor development | Exon 2 skipping (IVS1_5 GtoA) | [95] |
NDUFA12 | Assembly/stability | Leigh syndrome, progressive loss of motor abilities, scoliosis, and dystonia | R60X (c.C178T) | [96] |
NDUFA13 | Assembly/stability | Delayed development, hypotonia, abnormal eye movements, and poor feeding | R57H (c.G170A) | [97] |
NDUFB3 | Assembly/stability | Myopathy, hypotonia, developmental delay, and lactic acidosis | G70X (c.G208T) W20R (c.T64C) | [79,98] |
NDUFB8 | Assembly/stability | Leigh syndrome, respiratory failure, seizures, hypotonia, cardiac hypertrophy, failure to thrive, and severely delayed psychomotor development | P76Q (c.C277A) C144W (c.C432G) | [99] |
NDUFB9 | Assembly/stability | Progressive hypotonia | R47L (c.G140T) L64P (c.T191C) | [100] |
NDUFB10 | Assembly/stability | Cardiomyopathy and lactic acidosis | E70X (c.206_207insT) C107S (c.T319C) | [101] |
NDUFB11 | Assembly/stability | Hypertrophic cardiomyopathy and lactic acidosis | W85X (c.G254A) S96P (c.C286T) Y108X (c.T320G) P110S (c.C328T) | [102,103] |
NDUFC2 | Assembly/stability | Leigh syndrome | H58L (c.A173T) c.346_*7del | [104] |
NDUFS1 | NADH oxidation | Growth retardation, axial hypotonia, and dystonia | R241W (c.C829T) D252G (c.A863G) M707V (c.T2227G) | [105] |
NDUFS2 | NADH oxidation | Neonatal lactic acidosis and hypertrophic cardiomyopathy | R228Q (c.G283A) P229Q (c.C686A) S413P (c.T1237C) | [106] |
NDUFS3 | NADH oxidation | Leigh syndrome, severe axial dystonia with oral and pharyngeal motor dysfunction, dysphagia, and tetraparetic syndrome | T145I (c.C434T) R199W (c.C595T) | [80] |
NDUFS4 | Assembly/stability | Muscular hypotonia, absence of visual and auditive attention, and cardiac defects | T96X (c.delG289) R106X (c.C316T) | [107] |
NDUFS6 | Assembly/stability | Fatal infantile lactic acidosis | C115Y (c.G344A) | [82] |
NDUFS7 | NADH oxidation | Leigh syndrome, feeding problems, dysarthria, and ataxia | V122M (c.G384A) | [108] |
NDUFS8 | NADH oxidation | Leigh syndrome, poor feeding, and episodes of apnea and cyanosis | P79L (c.C236T) R102H (c.G305A) | [109] |
NDUFV2 | NADH oxidation | Hypertrophic cardiomyopathy and truncal hypotonia | Exon 2 skipping (c.IVS2+5_+8del) | [110] |
Complex I Assembly Proteins | ||||
ACAD9 | Assembly | Myalgia, hypotonia, hypertrophic cardiomyopathy, and severe lactic acidosis | L98S (c.T223A) A220V (c.C659T) R414C (c.C1240T) R532T (c.C1594T) | [111,112,113,114,115] |
FOXRED1 | Assembly | Leigh syndrome, congenital lactic acidosis, athetoid movements of the limbs in early childhood, and hypotonia | Q323X (c.C694T) N430S (c.A1289G) | [116] |
NUBPL | Assembly | Developmental delay, short stature, myopathy, nystagmus, and ataxia | G56R (c.G166A) L104P (c.T311C) F242L (c.C726G) | [117] |
NDUFAF1 | Assembly | Hypertrophic cardiomyopathy, developmental delay, lactic acidosis, and hypotonia | T207P (c.A1001C) K253R (c.A1140G) | [118] |
NDUFAF2 | Assembly | Ataxia, lethargy, nystagmus, and hypotonia | R45X (c.C182T) | [119] |
NDUFAF3 | Assembly | Axial hypotonia, no eye contact, and wide anterior fontanel | G77R (c.G229C) R122P (c.G365C) | [120] |
NDUFAF4 | Assembly | Cardiomyopathy | L65P (c.T194C) | [120,121] |
NDUFAF6 | Assembly | Focal seizures, decreased movement and strength, ataxia, lactic acidosis, and Leigh syndrome | Q99R (c.A296G) | [122] |
NDUFAF8 | Assembly | Leigh syndrome | F18SfsX32 (C.45_52Ddup) F55L (c.C165G) | [123] |
TIMMDC1 | Assembly | Infantile-onset hypotonia, delayed or minimal psychomotor development, dysmetria, dyskinetic movements, nystagmus, and Leigh syndrome | R255X (c.C673T) | [124] |
TMEM126B | Assembly | Exercise intolerance, muscle weakness, myalgia, and hypertrophic cardiomyopathy | Q70X (c.C208T) D133N (c.G397A) G212V (c.G635T) | [125,126] |
Complex II Subunits | ||||
SDHA | Succinate oxidation | Leigh syndrome and neonatal dilated cardiomyopathy | G355E (c.G1700A) A524V (c.C1607T) | [127,128,129,130] |
SDHAF1 | Assembly factor | Spastic quadriplegia and psychomotor regression | R55P (c.G164C) G355E (c.G1700A) | [131] |
Complex III Subunits | ||||
MTCYB | Catalytic subunit | Exercise intolerance, encephalomyopathy, and cardiomyopathy | G166X (m.G15242A) G166E (m.G15243A) G251C (m.G15498A) G290D (m.G15615A) L13fsX50 (m.1478del4) | [132,133,134,135,136,137] |
BCS1L | Assembly factor | Muscle weakness, Leigh syndrome, and myopathy | T50A (c.A148G) D103IfsX8 (c.A306T) E133DfsX23 (c.399delA) | [136,138,139] |
LYRM7 | Chaperon protein | Progressive weakness, severe psychomotor regression, generalized hypotonia, inability to walk, and severe spastic tetraparesis | D25N (c.G73A) | [140] |
TTC19 | Assembly factor | Ataxia and spastic paraparesis | Q173X (c.C517T) L219X (c.T656G) Q277X (c.C829T) | [131,141] |
UQCC3 | Assembly factor | Hypotonia, delayed development, and lactic acidosis | V20E (c.T59A) | [142] |
UQCRFS1 | Catalytic subunit | Cardiomyopathy | V14D(c.T41A) R204X (c.C610T) V72_81del10 (c.G215-1C) | [143] |
UQCRQ | Binds and stabilization of cytochrome c | Leigh-like syndrome, severe psychomotor retardation, dystomia, and ataxia | S45F (c.C208T) | [144] |
Complex IV Subunits | ||||
MT-CO1 | Reduction of O2 to H2O | MELAS, myopathy, myoglobinuria, motor neuron disease, exercise intolerance, epilepsy, and Leigh syndrome | G226X (m.G6578A) Q232K (m.C6597A) K265fs271X (m.A6698del) G351D (m.G6955A) | [145,146,147,148,149] |
MT-CO2 | Acceptor of electrons from cyt c | Encephalomyopathy, myopathy, and hypertrophic cardiomyopathy | M1T (m.T7587C) K29M (m.T7671A) M153X (m.8042delAT) L168X (m.8088delT) | [150,151,152,153] |
MT-CO3 | Putative oxygen uptake regulator | Myopathy, muscle weakness, exercise intollerance, and seizures | W58X (m.G9379A) V91A (m.T9478C) P118QfsX124 (m.9559del) W248X (m.G9952A) | [154,155,156,157] |
SURF-1 | Assembly factor | Leigh syndrome, Charcot–Marie–Tooth disease | P119L (c.C356T) N178fsX8 (c.531_534del) R192W (c.C574T) Q251X (c.C751T) | [158,159,160,161] |
SCO-1 | Assembly factor | Hypotonia and cardiomyopathy | G124E (c.C385G) Q251X (c.C751T) | [162] |
SCO-2 | Metallochaperone | Fatal infantile cardioencephalomyopathy, hypotonia, HCMP, and Charcot–Marie–Tooth disease | Q53X (c.158T) E140K (c.G418A) P169T (c.C505A) S225F (c.C674T) | [163,164] |
Complex V Subunits | ||||
MT-ATP6 | Participation in the unidirectional H+ transfer | MILS, ataxia, and Charcot–Marie–Tooth disease | I24T (m.T8597C) P136S (m.C8932T) | [165,166,167,168,169,170] |
MT-ATP8 | Assembly/stability | Epilepsy, tetralogy of Fallot, weakness, infantile cardiomyopathy, hypertrophic cardiomyopathy, and ataxia | P39L (m.C8481T) W55R (m.T8528C) W55X (m.G8529A) | [168,169,170,171,172,173,174] |
Gene | Protein Name | Associated Neuromuscular Phenotype(s) | Pathogenic Mutation(s) | Reference(s) |
---|---|---|---|---|
SLC25A1 | Citrate carrier (CIC) | Congenital myastenic syndrome | R247Q (c.G740A) G130D (c.G389G) R282H (c.G845G) R210X (c.C628C) V49M (c.G145GA) | [233,234,235,236] |
SCL25A3 | Phosphate carrier (PIC) | Cardiac and skeletal myopathy | c.158-9A>G G72E (c.G215A) L200W (c.T599G) G296_S300delinsQIP (c.886-898delins7) | [237,238,239,240] |
SLC25A4 | ADP/ATP carrier isoform 1 (AAC1) | Adult onset progressive external ophtalmoplegia, adult onset cardiomyopathy, skeletal myopathy, and childhood onset mild myopathy | A80H (c.G239A) R235G (c.C703G) K33Q (c.A97T) A123D (c.C368A) | [231,241,242,243,244,245] |
SLC25A12 | Aspartate/glutamate carrier isoform 1 (AGC1) | Hypotonia, epilepsy, hypomyelination, muscle weakness, and inflammatory myopathy | R252Q (c.G1058A) Q590R (c.A1769G) T444I (c.C1331T) | [246,247] |
SLC25A20 | Carnitine/acylcarnitine carrier (CAC) | Muscle weakness, hypotonia, cardiomyopathy, and respiratory distress | Q238R (c.A713G) R275Q (c.G824A) | [248,249] |
SLC25A21 | 2-Oxodicarboxylate carrier (ODC1) | Spinal motor atrophy-like disease | K232R (c.A695G) | [250] |
SLC25A32 | Folate transporter (MFT) | Excercise intolerance, early onset ataxia, myoclonic dysarthria, and muscle weakness | c.-264_31delins14 W142X (c.G425A) R147L (c.G440A) | [251,252] |
SLC25A42 | Coenzyme A transporter | Developmental delay, encephalomyopathy, mild and severe motor impairment, and myopathy | N291D (c.A871G) c.380 +2T>A F173_175RFS (c.522_524del) | [253,254,255] |
SLC25A46 | SLC25A46 | Type 2 Charcot–Marie–Tooth neuropathy, Leigh syndrome, and progressive myoclonic ataxia | T142I (c.C425T) R246X (c.A736T) L348P (c.T1022C) R340C (c.C1018T) E335D (c.A1005T) L138R (c.T413G) | [256,257] |
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Marra, F.; Lunetti, P.; Curcio, R.; Lasorsa, F.M.; Capobianco, L.; Porcelli, V.; Dolce, V.; Fiermonte, G.; Scarcia, P. An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases. Biomolecules 2021, 11, 1633. https://doi.org/10.3390/biom11111633
Marra F, Lunetti P, Curcio R, Lasorsa FM, Capobianco L, Porcelli V, Dolce V, Fiermonte G, Scarcia P. An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases. Biomolecules. 2021; 11(11):1633. https://doi.org/10.3390/biom11111633
Chicago/Turabian StyleMarra, Federica, Paola Lunetti, Rosita Curcio, Francesco Massimo Lasorsa, Loredana Capobianco, Vito Porcelli, Vincenza Dolce, Giuseppe Fiermonte, and Pasquale Scarcia. 2021. "An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases" Biomolecules 11, no. 11: 1633. https://doi.org/10.3390/biom11111633