Table 1.
Impaired mitochondrial respiratory complex subunits associated with neuromuscular phenotypes. Their amino acids and nucleotide mutations are also reported.
| 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] |
MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MILS: maternally inherited Leigh syndrome; HCMP: hypertrophic cardiomyopathy; IVS: intervening sequence.