Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Lefkothea Papadopoulou
 -- 3270 2023-01-21 17:46:54 |
2 format correct
Jessie Wu
+ 4 word(s) 3274 2023-01-28 04:15:30 | |
3 format correct
Jessie Wu
Meta information modification 3274 2023-01-28 04:16:51 | |
4 format correct
Jessie Wu
+ 5 word(s) 3279 2023-01-28 04:18:31 | |
5 format correct
Jessie Wu
Meta information modification 3279 2023-01-28 04:19:20 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Foltopoulou, P.F.;  Miliotou, A.N.;  Ingendoh-Tsakmakidis, A.;  Tsiftsoglou, A.S.;  Vizirianakis, I.S.;  Pappas, I.S.;  Papadopoulou, L.C. Mitochondrial Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/40470 (accessed on 26 April 2024).
Foltopoulou PF,  Miliotou AN,  Ingendoh-Tsakmakidis A,  Tsiftsoglou AS,  Vizirianakis IS,  Pappas IS, et al. Mitochondrial Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/40470. Accessed April 26, 2024.
Foltopoulou, Parthena F., Androulla N. Miliotou, Alexandra Ingendoh-Tsakmakidis, Asterios S. Tsiftsoglou, Ioannis S. Vizirianakis, Ioannis S. Pappas, Lefkothea C. Papadopoulou. "Mitochondrial Disorders" Encyclopedia, https://encyclopedia.pub/entry/40470 (accessed April 26, 2024).
Foltopoulou, P.F.,  Miliotou, A.N.,  Ingendoh-Tsakmakidis, A.,  Tsiftsoglou, A.S.,  Vizirianakis, I.S.,  Pappas, I.S., & Papadopoulou, L.C. (2023, January 21). Mitochondrial Disorders. In Encyclopedia. https://encyclopedia.pub/entry/40470
Foltopoulou, Parthena F., et al. "Mitochondrial Disorders." Encyclopedia. Web. 21 January, 2023.
Mitochondrial Disorders
Edit
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15010286

Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human synthesis of cytochrome c oxidase 2 (SCO2) gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. 

Sco2 COX deficiency mitochondria mitochondrial disorders encephalomyopathies cardiac hypertrophy

1. Mitochondria: Characteristics and Function

It has been over 150 years since the discovery of the mitochondrion, the double-membrane intracellular organelle with critical roles in multiple cellular and metabolic pathways [1][2]. Still, the interest for medicinal applications targeting deficiency of their function has mostly been undertaken for the last three (3) decades.
These essential semi-autonomous organelles consist of two membranes, i.e., the outer (OMM) and the inner (IMM) mitochondrial membrane, separated by a small intermembrane soluble space (IMS). The two membranes have different architecture and permeability properties, where the OMM allows the passage of small proteins and ions, while the IMM is more restricted towards permeabilization. The IMM folds over many times and creates layered structures called cristae, which extend into the interior soluble compartment (the matrix) of the organelle [3][4]. The main function of mitochondria in eukaryotic cells is the production of chemical energy through the oxidative phosphorylation (OXPHOS) pathway [5][6]. This metabolic energy-generating pathway is embedded in the inner mitochondrial membrane and under normal physiological conditions produces more than 90% of the cellular energy. Moreover, in the matrix, metabolic pathways such as the β-oxidation of fatty acids, the tricarboxylic acid cycle (TCA or citric acid cycle or Krebs cycle), as well the urea cycle take place. Other cellular processes in which mitochondria are implicated include the initiation of apoptosis (programmed cell death) [7][8], calcium homeostasis [9], heme and iron–sulfur cluster biosynthesis [10], amino acid and lipid metabolism [11], and generation of reactive oxygen species (ROS) [12][13].
Mitochondria are highly dynamic organelles with their own set of DNA, called mitochondrial DNA (mtDNA), of which each mitochondrion in humans can have two to ten copies of circular DNA. It is widely believed that these organelles were once primitive bacteria with their own DNA that were swallowed up by larger cells more than a billion years ago. As these bacteria and their host cells evolved, they developed a co-dependent relationship [14]. Through evolution, many of the mitochondrial genes either were lost or transferred to nucleus [15]; thus, the mitochondrial proteome is derived from both mitochondrial and nuclear DNA (nDNA). mtDNA is a highly compact, circular, double-stranded, haploid DNA strand molecule of 16,569 base pairs (bp) in humans, lacking introns and containing 37 genes that encode 13 structural subunits of the OXPHOS system (complexes I, III, IV, and V) and 22 tRNAs necessary for intramitochondrial protein synthesis and the small (12S) and large (16S) ribosomal RNAs (rRNAs) [16]. The organization of the mammalian mitochondrial genome is highly conserved [17], while only 3% of the mtDNA (the D-loop area of the 1.1 kilobases (kb) in humans) is a non-coding region and contains elements crucial for its replication and transcription [18]. The mitochondrial DNA is replicated, transcribed, and translated within the matrix space, with a modified mitochondrial genetic code differing from the universal one in four codons [19], and it is maternally inherited [20].
The number of mitochondria in cells varies between organisms, tissues, and cell types and depends mainly on their metabolic needs. These numbers range per cell from a single large mitochondrion to thousands of organelles. In humans, erythrocytes (mature red blood cells) are the only cells that lack mitochondria, while organs with high demands for energy production, such as heart, muscle, liver, kidney, and to a certain extent the brain, can have hundreds or thousands of these organelles in each cell.

2. Oxidative Phosphorylation Pathway

The OXPHOS pathway, i.e., the electron transport-linked phosphorylation, is a metabolic pathway responsible for producing chemical energy in the form of adenosine trisphosphate (ATP). This pathway consists of five multi-subunits protein complexes and two mobile electron carriers (coenzyme Q (CoQ) and cytochrome c). OXPHOS generates an electrochemical transmembrane gradient through the first four multi-protein complexes (I–IV), which consist the mitochondrial respiratory chain (MRC) that fuels ATP synthesis through the last complex (V) of OXPHOS, the ATP synthase complex [5]. In this pathway, the two electron donors (the reduced nicotinamide dinucleotide (NADH) and the reduced flavin adenine dinucleotide (FADH2)), which are products of the glycolysis, the β-oxidation of fatty acids, and the TCA cycle, start passing along electrons during oxidation to complex I (ubiquinone oxidoreductase-NADH) or complex II (succinate dehydrogenase), respectively, and then to electron carrier coenzyme Q or ubiquinone. Reduced ubiquinol transfers electrons to complex III (ubiquinol: cytochrome c oxidoreductase) and, more specifically, to cytochrome c1. Then, the second soluble electron carrier, cytochrome c, transfers the electrons to complex IV (cytochrome c oxidase or COX), which catalyzes molecular oxygen (O2) to water (H2O) at the final stage. The downstream transport of electrons results in a proton gradient as protons are pumped into the intermembrane space, thus providing the energy to ATP synthase (complex V) to convert adenosine diphosphate (ADP) and inorganic phosphate (Pi) into ATP.
While the complexes I, III, IV, and V are under dual genomic control since their structural proteins are encoded from both genomes, complex II’s structural proteins are encoded only by the nDNA. Additionally, numerous ancillary proteins called assembly factors (all being encoded by the nDNA) are necessary for the biogenesis and assembly of the five multi-subunits complexes of OXPHOS.

3. The Mitochondrial Machinery for Protein Import and Assembly

Although mitochondria have their own DNA, less than 1% (13 structural subunits of OXPHOS) of the roughly 1500 mitochondrial proteins are produced in the matrix. The vast majority of the mitochondrial proteome is encoded by the nDNA (spread across most chromosomes) and expressed as protein precursors (preproteins) in the cytosol. The mitochondrial preproteins either carry a cleavable mitochondrial targeting signal (MTS) peptide in their sequence or various internal targeting signals, which in both cases guide them to the mitochondria. The MTS peptide (predicted by the Mitoprot logistic program: https://ihg.helmholtz-muenchen.de/ihg/mitoprot.html, accessed on 1 November 1996) or leader peptide (L) is typically a 15–50 amino acid (aa) peptide, mostly in the N-terminus of the protein precursors, with some exceptions found in C-terminus [21]. Cytosolic chaperones facilitate the transfer of the preproteins to the general entry gate of mitochondria, the translocase of the outer membrane (TOM) complex. Nearly all mitochondrial preproteins are imported via the TOM complex, and they are subsequently sorted into one of the mitochondrial sub-compartments using the mitochondrial protein import-sorting machinery. Depending on the final destination of mitochondrial proteins, Pfanner’s group [22] suggests five major protein import pathways. The majority of matrix proteins and inner-membrane proteins, which are synthesized with N- (or C-) terminal cleavable MTS peptides (pre-sequences), utilize the classical import pathway (or pre-sequence pathway) consisting of the TOM complex, the translocase of the inner membrane (TIM23), and the pre-sequence translocase-associated motor (PAM). Once these preproteins enter into the matrix, the mitochondrial processing peptidase (MPP) [23] cleaves off the MTS peptides. Pre-proteins with internal targeting signals utilize the other four (4) described pathways, with the final destination defining which of the pathways will be employed. Components of these pathways are the small TIM chaperones of the intermembrane space, the carrier translocase of the intermembrane space, the translocase of the inner membrane (TIM22), the sorting assembly machinery (SAM), the mitochondrial intermembrane space import and assembly (MIA), translocase of the inner membrane (TIM), and the mitochondrial import complex (MIM). Ongoing research will probably reveal additional import routes and complexity given that the pathways responsible for several precursor proteins remain still un-identified.

4. Mitochondrial Genetic Disorders

While mitochondrial disorders represent a heterogeneous group of rare inherited genetic disorders with varying severity and clinical outcomes, they are generally characterized by respiratory chain dysfunction and abnormal mitochondrial function. The overall estimated prevalence of these disorders is one to three cases per 20,000 individuals [24], with lifelong symptoms that can appear from very early (newborn) to later in life. Unsurprisingly, mitochondrial disorders often affect organs with high metabolic needs such as muscles, heart, liver, kidneys, central nervous system (CNS), peripheral nervous system (PNS), as well sensory organs (eyes and ears) [13][25]. It has been reported that some mitochondrial disorders can affect only a single organ (as in Leber hereditary optic neuropathy (LHON) [26] and in mitochondrial non-syndromic hearing loss and deafness), but often, these disorders cause multi-system dysfunction.
Primary mitochondrial disorders (PMDs) are genetic disorders caused by pathogenic variants in either mitochondrial or nuclear genes coding for mitochondrial respiratory chain and related proteins. The first time that mitochondrial disorder was reported was in 1962 [27] in a patient with severe hypermetabolism, while in 1988, the first mutations in mtDNA were associated with human disease [26][28]. Since then, pathogenic variants in more than 400 genes of both mitochondrial and nuclear origin have been reported in primary mitochondrial disorders.
Mitochondrial dysfunction has also been observed in numerous neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Friedreich’s ataxia (FRDA); in age-related disorders; in metabolic disorders; as well in traumatic brain injury, ischemic stroke, and in a wide spectrum of human cancers [6][15][29].

4.1. Mitochondrial Disorders Attributed to Genes Encoded by mtDNA

The mtDNA is highly polymorphic among individuals (~50–60 neutral polymorphisms between two individuals). The lack of protective histones and limited repair mechanisms make the mitochondrial genome highly susceptible to oxidative damage [30][31], with an estimated mutation rate 10–20 times higher than that of nDNA [32]. Mutations in mtDNA include: (a) large-scale rearrangements (single deletions or duplications) that are always heteroplasmic and (b) point mutations (either homo- or heteroplasmic). In the latter, pathogenic point mtDNA mutations frequently coexist with wild-type (w/t) mtDNA (a phenomenon termed heteroplasmy), with higher levels of mutation accumulating in post-mitotic tissues such as skeletal muscle, heart, and the central nervous system [33]. In these cases, individuals develop symptoms/clinical phenotype when the mutated mtDNA exceeds a threshold level (usually 60–90%) compared to normal [34]. Interestingly, family members may have different levels of mutated mtDNA, and even individuals may experience different levels of mutated mtDNA in different organs and tissues [35].
  • Large-scale rearrangements are associated with:
    • Sporadic progressive external ophthalmoplegia (PEO) [36];
    • Kearns–Sayre syndrome (KSS) [36];
    • Pearson’s syndrome [37];
    • Leigh syndrome (LS) (rarely) [38][39]
  • Homoplasmic point mutations are associated with:
    • Leber hereditary optic neuropathy (LHON) [26]
  • Heteroplasmic point mutations are associated with:
    • Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [40];
    • Myoclonic epilepsy with ragged red fibers (MERRF) [41];
    • Neurogenic weakness ataxia and retinitis pigmentosa (NARP) [42];
    • Leigh syndrome (LS) [38][39]

4.2. Mitochondrial Disorders Attributed to Genes Encoded by nDNA

Mitochondrial disorders can also be caused by mutations in nDNA, specifically in genes that encode either (a) structural proteins of the core subunits of the mitochondrial respiratory chain (complex I–IV) and ATP synthase complex V [43] or (b) no-structural proteins [44]. The second category includes: (i) assembly factors of the respiratory complexes; (ii) proteins responsible for the transcription and translation of mtDNA; (iii) proteins involved in mtDNA replication and maintenance of its integrity and abundance; (iv) proteins necessary for mitochondrial import; (v) proteins involved in iron homeostasis as well as in coenzyme Q10 biogenesis; and (vi) proteins involved in mitochondrial metabolism.

5. Cytochrome c Oxidase (COX) Deficiency

COX, the terminal enzyme of mitochondrial respiratory chain, is a 14-subunit holoenzyme that catalyzes the electron transfer from reduced cytochrome c to molecular oxygen in order to produce water and thus facilitates the generation of the proton gradient across the inner mitochondrial membrane that is used to synthesize ATP [45][46]. This electron transfer occurs through COX’s redox centers, two heme A moieties (a and a3), and two copper centers (CuA and CuB) [47][48].
Three of the COX’s subunits are encoded by the mtDNA (MT-CO1, MT-CO2, and MT-CO3), and form the catalytic core of the holoenzyme, while the remaining eleven (COX4, COX5A, COX5B, COX6A, COX6B, COX6C, COX7A, COX7B, COX7C, COX8, and NDUFA4/COXFA4 [46][49]) are encoded by nDNA. Interestingly, some of the nuclear encoded subunits of COX (4, 6A, 6B, 7A, 7B, and 8A) appear with different isoforms that are tissue-, developmental-, and species-specific isoforms [50]. The heme a and the heme a3-CuB binuclear centers are associated with MT-CO1, whereas MT-CO2 contains the CuA center [51]. Additional, around 30 nDNA-encoded ancillary factors, including copper chaperones, also called COX-assembly proteins, are involved in the biogenesis and assembly of COX holoenzyme. To date, mutations in the subunits encoded by both genomes have been associated with disorder (MT-CO1 [52], MT-CO2 [53], MT-CO3 [54], COX4I1 [55], COX4I2 [56], COX5A [57], COX6A1 [56][58], COX6A2 [56][59], COX6B1 [60], COX7A1 [56], COX7A2 [56], COX7B [61], COX8A [62], and NDUFA4 or COXFA4 [63]), while the majority of isolated COX deficiencies are caused by mutations in COX assembly factors. Specifically, disorder-causing mutations were found in genes such as SURF1 (the first identified nuclear gene encoding a factor involved in the biogenesis of COX and being mutated in the neurodegenerative Leigh’s syndrome with COX deficiency) [64][65]; SCO2/SCO1 (involved in mitochondrial copper pathway) [66][67]; COX10 and COX15 (involved in heme A biosynthesis) [68][69][70]; COX14 (or C12ORF62; involved in COX assembly) [71]; COX20 (or FAM36A; involved in MT-CO2 stabilization) [72]; COA3 (CCDC56 or MITRAC12; involved in MT-CO1 maturation) [73]; PET100 (involved in COX biogenesis) [74]; PET117 (involved in the assembly of MT-CO2) [75]; COA5 (C2ORF64) [76]; COA6 [77]; COA7 [78]; COA8 (previously known as APOPT1) [79]; FASTKD2 [80]; LRPPRC; and TACO1 (essential for COX expression) [81][82].

6. Synthesis of Cytochrome C Oxidase 2 

The synthesis of cytochrome c oxidase 2 (SCO2) gene is located on chromosome 22 (22q13.33), and it encodes a precursor mitochondrial protein of 266aa. This precursor protein (full length) harbors a mitochondrial targeting sequence (MTS or L) on its N-terminus (1-41aa) that facilitates its transportation to mitochondria and, more specifically, to the inner mitochondria membrane. Sco2 protein acts as assembly factor of COX (complex IV) and is involved in the biogenesis of COX subunit II (MT-CO2), an essential core subunit of complex IV [83]. Sco2 contains a highly conserved copper-binding motif (CXXXC), and acting as metallochaperone, it participates in transport of copper to the Cu(A) site of ΜΤ-CO2 along with Sco1 homolog protein and Coa6, downstream of Cox17 [84][85][86][87][88][89]. In addition, Sco2 acts as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in Sco1 [90]. Sco2 protein is also involved in mitochondrial redox signaling [91] and the p53 regulatory pathway in mitochondria [92][93].
Mutations in SCO2 are often reported in cases of COX deficiency and have been associated with severe phenotypes and different clinical outcomes, such as myopathies, cardiac hypertrophy, neuropathies, and Leigh syndrome [66][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121]. Initially, mutations in SCO2 were found in three unrelated infants with fatal cardioencephalomyopathy and COX deficiency [66]. To date, nearly 100 patients with pathogenic variations in the SCO2 gene have been reported (Table 1). A recurrent p.Glu140Lys (E140K) mutation has been described in at least one allele in the majority of the patients, raising the possibility of a hot-spot mutation. Patients homozygous for the E140K mutation have a delayed onset of disorder and longer survival compared with patients compound heterozygous for the E140K mutation [122]. Characterization of the E140K mutation in Sco2 protein from researcher's group [84] revealed decreased affinity to copper when compared to the w/t Sco2 protein.
Table 1. Reported Sco2 mutations and associated pathologies.
SCO2 Genotype Clinical Outcome Affected
Individual(s)		 References *
Q53X/E140K Fatal infantile cardioencephalomyopathy with COX deficiency, neurological
symptoms with lactic/metabolic acidosis,
respiratory difficulties		 6 Papadopoulou L.C. et al., 1999 [66];
Tay S.K.H. et al., 2004 [110];
Vesela K. et al., 2004 [113];
Pronicki M. et al., 2010 [103];
Pronicka E. et al., 2013 [102]
E140K/S225F Fatal infantile cardioencephalomyopathy with COX deficiency 1 Papadopoulou L.C. et al., 1999 [66]
E140K/R171W Fatal hypertrophic cardiomyopathy (HCMP), seizures, muscle hypotonia (MH), respiratory insufficiency 1 Jaksch M. et al., 2000 [97]
R90X/E140K Fatal hypertrophic cardiomyopathy (HCMP), seizures, muscle hypotonia (MH), respiratory insufficiency 2 Jaksch M. et al., 2000 [97]
E140K/E140K Delayed infantile onset of cardiomyopathy and neuropathy,
laryngeal inspiratory stridor,
infantile SMA-like/Leigh-like picture		 39 Jaksch M. et al., 2001 [122];
Vesela K. et al., 2004 [113];
Bohm M. et al., 2006 [118];
Pronicki M. et al., 2010 [103];
Pronicka E. et al., 2013 [102]
10 bp duplication (1302–1311)/E140K Prominent spinal cord involvement
mimicking spinal muscular atrophy (Werdnig–Hoffmann disease)		 1 Salviati L. et al., 2002 [106]
E140K/L151P Hypertrophic cardiomyopathy and
encephalomyopathy		 1 Sacconi S. et al., 2003 [105]
C133S/E140K Neonatal hypotonia with a spinal muscular atrophy (SMA) type 1 phenotype 1 Tarnopolsky M.A. et al., 2004 [109]
1518delA/E140K Cytochrome c oxidase deficiency and a Werdnig–Hoffmann disease phenotype 2 Bohm M. et al., 2006 [118];
Vesela K. et al., 2008 [114];
Hemizygosity 16 bp deletion within the intron_E140K Early onset rapidly progressive, fatal
cardiomyopathy		 1 Leary S.C. et al., 2006 [100]
E140K/V160G Cytochrome c oxidase deficiency, fatal
infantile cardioencephalomyopathy		 1 Knuf M. et al., 2007 [99]
W36X/E140K Fatal infantile cardioencephalomyopathy 2 Verdijk R.M. et al., 2008 [112]
G193S/G193S Fatal infantile cardioencephalomyopathy 1 Mobley B.C. et al., 2009 [101]
E140K/M177T Classical SMA or SMA-like picture,
laryngeal inspiratory stridor,
milder encephalopathic		 4 Pronicki M. et al., 2010 [103];
Pronicka E. et al., 2013 [102]
E140K/w/t Respiratory failure, artificial ventilation,
hypotony, high-grade myopia		 4 Pronicki M. et al. 2010 [103];
Tran-Viet K.N. et al. 2013 [111]
19 bp insertion at position 17 (17INS19bp)/
E140K		 Failure to thrive, muscular hypotonia,
hypertrophic cardiomyopathy, and lactic acidemia, totally absent of COX activity		 1 Joost K. et al., 2010 [98]
12 bp deletion (c.1519_1530del)/
E140K		 Cardioencephalomyopathy,
stridor, neuropathy		 1 Gurgel-Giannetti J. et al., 2013 [96]
Q53X/w/t High-grade myopia 7 Tran-Viet K.N. et al., 2013 [111]
R114H/w/t High-grade myopia 1 Tran-Viet K.N. et al. 2013 [111]
p82delK/E140K Progressive encephalopathy, cardiomegaly, spinal muscular atrophy, COX deficiency 1 Pronicka E. et al., 2013 [102]
W75R/E140K Neonatal cardiomyopathy,
muscle weakness		 1 Pronicka E. et al., 2013 [102]
E140K/T241X Neonatal cardiomyopathy, muscle
weakness, Leigh disease		 1 Pronicka E. et al., 2013 [102]
V160A/P233T Fatal hyperthermia and metabolic acidosis 1 Sambuughin N. et al., 2013 [107]
A259V/w/t High-grade myopia 1 Tran-Viet K.N. et al., 2013 [111]
D223N/87 kb deletion on chr.22 Severe hypotonic syndrome, failure to thrive, divergent strabismus and ataxia,
regression of psychomotor development		 1 Vondrackova A. et al., 2014 [115]
R112W/w/t Early-onset high myopia 1 Jiang D. et al., 2014 [119]
R120W/w/t Early-onset high myopia 1 Jiang D. et al., 2014 [119]
A97V/w/t Extreme myopia 1 Wakazono T. et al., 2016 [117]
D135G/R171Q Early-onset axonal Charcot–Marie–Tooth disease associated with cellular copper
deficiency		 1 Rebelo A.P. et al., 2018 [104]
E140K/P169T Early-onset axonal Charcot–Marie–Tooth disease associated with cellular copper
deficiency		 1 Rebelo A.P. et al., 2018 [104]
D173V/w/t Non-syndromic high myopia 1 Cai X.B. et al., 2019 [120]
A201P/w/t Non-syndromic high myopia 1 Cai X.B. et al., 2019 [120]
I221V/w/t Non-syndromic high myopia 1 Cai X.B. et al., 2019 [120]
R255W/R255W Cerebellar ataxia, progressive peripheral
axonal neuropathy and long survival		 2 Barcia G. et al., 2019 [94]
p82delK/w/t Non-syndromic high myopia 1 Zheng Y.H et al., 2021 [121]
R60Q/G193S Adult cerebellar ataxia, axonal
neuropathy, and sensory impairments		 1 Rucheton B. et al., 2021 [116]
G121R/G121R Early-onset axonal Charcot–Marie–Tooth disease 2 Gangfuß A. et al., 2022 [95]
* Sco2 mutants are shown in chronological order based on their first report.
Homozygous deletion of SCO2 mice (knock-out mice SCO2KO/KO) is embryonic-lethal [123]. Heterozygous SCO2 knock-out/knock-in (SCO2KO/KI) mice carrying a SCO2 knock-out (KO) allele and a SCO2 knock-in (KI) allele with the missense mutation E129K (corresponding to the E140K mutation found in almost all human SCO2-mutated patients) and homozygous SCO2 knock-in mice (SCO2KI/KI) carrying the missense mutation E129K in both alleles have been shown to be viable and fertile despite the muscle weakness and reduction in COX activity [123]. Additionally, heterozygous SCO2KO/KI mice have increased fat mass associated with reduced β-oxidation and increased adipogenesis markers, reduced insulin receptor beta (IR-β levels in adipose tissue), reduced muscle glucose transporter 4 (Glut4) levels, and an impaired response to the insulin-tolerance test consistent with insulin resistance [124]. Even though these mice models do not recapitulate human disorder, they are still a valuable preclinical tool for testing new therapeutic approaches for COX deficiencies.

References

  1. Ernster, L.; Schatz, G. Mitochondria: A historical review. J. Cell Biol. 1981, 91 Pt 2, 227s–255s.
  2. Spinelli, J.B.; Haigis, M.C. The multifaceted contributions of mitochondria to cellular metabolism. Nat. Cell Biol. 2018, 20, 745–754.
  3. Palade, G.E. An electron microscope study of the mitochondrial structure. J. Histochem. Cytochem. 1953, 1, 188–211.
  4. Kuhlbrandt, W. Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015, 13, 89.
  5. Saraste, M. Oxidative phosphorylation at the fin de siecle. Science 1999, 283, 1488–1493.
  6. Wallace, D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu. Rev. Genet. 2005, 39, 359–407.
  7. Wang, C.; Youle, R.J. The role of mitochondria in apoptosis*. Annu. Rev. Genet. 2009, 43, 95–118.
  8. Tait, S.W.; Green, D.R. Mitochondrial regulation of cell death. Cold Spring Harb. Perspect. Biol. 2013, 5, a008706.
  9. Modesti, L.; Danese, A.; Angela Maria Vitto, V.; Ramaccini, D.; Aguiari, G.; Gafa, R.; Lanza, G.; Giorgi, C.; Pinton, P. Mitochondrial Ca(2+) Signaling in Health, Disease and Therapy. Cells 2021, 10, 1317.
  10. Ye, H.; Rouault, T.A. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 2010, 49, 4945–4956.
  11. Wang, W.; Li, L.; Wang, X. Therapeutic targets during mitochondrial lipid metabolism. Cell Biol. Toxicol. 2020, 36, 205–208.
  12. Chandel, N.S. Mitochondria as signaling organelles. BMC Biol. 2014, 12, 34.
  13. Protasoni, M.; Zeviani, M. Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions. Int. J. Mol. Sci. 2021, 22, 586.
  14. Sagan, L. On the origin of mitosing cells. J. Theor. Biol. 1967, 14, 255–274.
  15. Singh, L.N.; Kao, S.H.; Wallace, D.C. Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury. Cells 2021, 10, 3460.
  16. Anderson, S.; Bankier, A.T.; Barrell, B.G.; de Bruijn, M.H.; Coulson, A.R.; Drouin, J.; Eperon, I.C.; Nierlich, D.P.; Roe, B.A.; Sanger, F.; et al. Sequence and organization of the human mitochondrial genome. Nature 1981, 290, 457–465.
  17. Clayton, D.A. Transcription and replication of animal mitochondrial DNAs. Int. Rev. Cytol. 1992, 141, 217–232.
  18. Clayton, D.A. Nuclear gadgets in mitochondrial DNA replication and transcription. Trends Biochem. Sci. 1991, 16, 107–111.
  19. Taanman, J.W. The mitochondrial genome: Structure, transcription, translation and replication. Biochim. Biophys. Acta 1999, 1410, 103–123.
  20. Giles, R.E.; Blanc, H.; Cann, H.M.; Wallace, D.C. Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA 1980, 77, 6715–6719.
  21. Lee, C.M.; Sedman, J.; Neupert, W.; Stuart, R.A. The DNA helicase, Hmi1p, is transported into mitochondria by a C-terminal cleavable targeting signal. J. Biol. Chem. 1999, 274, 20937–20942.
  22. Wiedemann, N.; Pfanner, N. Mitochondrial Machineries for Protein Import and Assembly. Annu. Rev. Biochem. 2017, 86, 685–714.
  23. Hawlitschek, G.; Schneider, H.; Schmidt, B.; Tropschug, M.; Hartl, F.U.; Neupert, W. Mitochondrial protein import: Identification of processing peptidase and of PEP, a processing enhancing protein. Cell 1988, 53, 795–806.
  24. Gorman, G.S.; Chinnery, P.F.; DiMauro, S.; Hirano, M.; Koga, Y.; McFarland, R.; Suomalainen, A.; Thorburn, D.R.; Zeviani, M.; Turnbull, D.M. Mitochondrial diseases. Nat. Rev. Dis. Primers 2016, 2, 16080.
  25. 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.
  26. Wallace, D.C.; Singh, G.; Lott, M.T.; Hodge, J.A.; Schurr, T.G.; Lezza, A.M.; Elsas, L.J., 2nd; Nikoskelainen, E.K. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988, 242, 1427–1430.
  27. Luft, R.; Ikkos, D.; Palmieri, G.; Ernster, L.; Afzelius, B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical, and morphological study. J. Clin. Investig. 1962, 41, 1776–1804.
  28. Holt, I.J.; Harding, A.E.; Morgan-Hughes, J.A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988, 331, 717–719.
  29. Rout, S.K.; Priya, V.; Setia, A.; Mehata, A.K.; Mohan, S.; Albratty, M.; Najmi, A.; Meraya, A.M.; Makeen, H.A.; Tambuwala, M.M.; et al. Mitochondrial targeting theranostic nanomedicine and molecular biomarkers for efficient cancer diagnosis and therapy. Biomed. Pharmacother. 2022, 153, 113451.
  30. Richter, C.; Park, J.W.; Ames, B.N. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc. Natl. Acad. Sci. USA 1988, 85, 6465–6467.
  31. Mecocci, P.; MacGarvey, U.; Kaufman, A.E.; Koontz, D.; Shoffner, J.M.; Wallace, D.C.; Beal, M.F. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann. Neurol. 1993, 34, 609–616.
  32. Brown, W.M.; George, M., Jr.; Wilson, A.C. Rapid evolution of animal mitochondrial DNA. Proc. Natl. Acad. Sci. USA 1979, 76, 1967–1971.
  33. Lightowlers, R.N.; Chinnery, P.F.; Turnbull, D.M.; Howell, N. Mammalian mitochondrial genetics: Heredity, heteroplasmy and disease. Trends Genet. 1997, 13, 450–455.
  34. Schon, E.A.; Bonilla, E.; DiMauro, S. Mitochondrial DNA mutations and pathogenesis. J. Bioenerg. Biomembr. 1997, 29, 131–149.
  35. Macmillan, C.; Lach, B.; Shoubridge, E.A. Variable distribution of mutant mitochondrial DNAs (tRNA(Leu)) in tissues of symptomatic relatives with MELAS: The role of mitotic segregation. Neurology 1993, 43, 1586–1590.
  36. Moraes, C.T.; DiMauro, S.; Zeviani, M.; Lombes, A.; Shanske, S.; Miranda, A.F.; Nakase, H.; Bonilla, E.; Werneck, L.C.; Servidei, S.; et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N. Engl. J. Med. 1989, 320, 1293–1299.
  37. Rotig, A.; Colonna, M.; Bonnefont, J.P.; Blanche, S.; Fischer, A.; Saudubray, J.M.; Munnich, A. Mitochondrial DNA deletion in Pearson’s marrow/pancreas syndrome. Lancet 1989, 1, 902–903.
  38. Leigh, D. Subacute necrotizing encephalomyelopathy in an infant. J. Neurol. Neurosurg. Psychiatry 1951, 14, 216–221.
  39. Rahman, S.; Thorburn, D. Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview. In GeneReviews((R)); Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993.
  40. Goto, Y.; Nonaka, I.; Horai, S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990, 348, 651–653.
  41. Shoffner, J.M.; Lott, M.T.; Lezza, A.M.; Seibel, P.; Ballinger, S.W.; Wallace, D.C. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990, 61, 931–937.
  42. Holt, I.J.; Harding, A.E.; Petty, R.K.; Morgan-Hughes, J.A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 1990, 46, 428–433.
  43. Structural Nuclear Genes for Mitochondrial Disorders. Available online: https://www.mitomap.org/foswiki/bin/view/MITOMAP/NuclearGenesStructural (accessed on 30 November 2022).
  44. Non-Structural Nuclear Genes for Mitochondrial Disorders. Available online: https://www.mitomap.org/bin/view.pl/MITOMAP/NuclearGenesNonStructural (accessed on 30 November 2022).
  45. Capaldi, R.A. Structure and function of cytochrome c oxidase. Annu. Rev. Biochem. 1990, 59, 569–596.
  46. Balsa, E.; Marco, R.; Perales-Clemente, E.; Szklarczyk, R.; Calvo, E.; Landazuri, M.O.; Enriquez, J.A. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 2012, 16, 378–386.
  47. Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.; Yamaguchi, H.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yoshikawa, S. Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A. Science 1995, 269, 1069–1074.
  48. Ishigami, I.; Zatsepin, N.A.; Hikita, M.; Conrad, C.E.; Nelson, G.; Coe, J.D.; Basu, S.; Grant, T.D.; Seaberg, M.H.; Sierra, R.G.; et al. Crystal structure of CO-bound cytochrome c oxidase determined by serial femtosecond X-ray crystallography at room temperature. Proc. Natl. Acad. Sci. USA 2017, 114, 8011–8016.
  49. Pitceathly, R.D.S.; Taanman, J.W. NDUFA4 (Renamed COXFA4) Is a Cytochrome-c Oxidase Subunit. Trends Endocrinol. Metab. 2018, 29, 452–454.
  50. Sinkler, C.A.; Kalpage, H.; Shay, J.; Lee, I.; Malek, M.H.; Grossman, L.I.; Huttemann, M. Tissue- and Condition-Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease. Oxid. Med. Cell. Longev. 2017, 2017, 1534056.
  51. Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.; Yamaguchi, H.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yoshikawa, S. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science 1996, 272, 1136–1144.
  52. Brown, M.D.; Voljavec, A.S.; Lott, M.T.; MacDonald, I.; Wallace, D.C. Leber’s hereditary optic neuropathy: A model for mitochondrial neurodegenerative diseases. FASEB J. 1992, 6, 2791–2799.
  53. Clark, K.M.; Taylor, R.W.; Johnson, M.A.; Chinnery, P.F.; Chrzanowska-Lightowlers, Z.M.; Andrews, R.M.; Nelson, I.P.; Wood, N.W.; Lamont, P.J.; Hanna, M.G.; et al. An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy. Am. J. Hum. Genet. 1999, 64, 1330–1339.
  54. Johns, D.R.; Neufeld, M.J. Cytochrome c oxidase mutations in Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 1993, 196, 810–815.
  55. Abu-Libdeh, B.; Douiev, L.; Amro, S.; Shahrour, M.; Ta-Shma, A.; Miller, C.; Elpeleg, O.; Saada, A. Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. Eur. J. Hum. Genet. 2017, 25, 1142–1146.
  56. Vondrackova, A.; Vesela, K.; Hansikova, H.; Docekalova, D.Z.; Rozsypalova, E.; Zeman, J.; Tesarova, M. High-resolution melting analysis of 15 genes in 60 patients with cytochrome-c oxidase deficiency. J. Hum. Genet. 2012, 57, 442–448.
  57. Baertling, F.; Al-Murshedi, F.; Sanchez-Caballero, L.; Al-Senaidi, K.; Joshi, N.P.; Venselaar, H.; van den Brand, M.A.; Nijtmans, L.G.; Rodenburg, R.J. Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. Hum. Mutat. 2017, 38, 692–703.
  58. Tamiya, G.; Makino, S.; Hayashi, M.; Abe, A.; Numakura, C.; Ueki, M.; Tanaka, A.; Ito, C.; Toshimori, K.; Ogawa, N.; et al. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 2014, 95, 294–300.
  59. Inoue, M.; Uchino, S.; Iida, A.; Noguchi, S.; Hayashi, S.; Takahashi, T.; Fujii, K.; Komaki, H.; Takeshita, E.; Nonaka, I.; et al. COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency. Ann. Neurol. 2019, 86, 193–202.
  60. Massa, V.; Fernandez-Vizarra, E.; Alshahwan, S.; Bakhsh, E.; Goffrini, P.; Ferrero, I.; Mereghetti, P.; D’Adamo, P.; Gasparini, P.; Zeviani, M. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am. J. Hum. Genet. 2008, 82, 1281–1289.
  61. Indrieri, A.; van Rahden, V.A.; Tiranti, V.; Morleo, M.; Iaconis, D.; Tammaro, R.; D’Amato, I.; Conte, I.; Maystadt, I.; Demuth, S.; et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am. J. Hum. Genet. 2012, 91, 942–949.
  62. Hallmann, K.; Kudin, A.P.; Zsurka, G.; Kornblum, C.; Reimann, J.; Stuve, B.; Waltz, S.; Hattingen, E.; Thiele, H.; Nurnberg, P.; et al. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain 2016, 139 Pt 2, 338–345.
  63. Pitceathly, R.D.; Rahman, S.; Wedatilake, Y.; Polke, J.M.; Cirak, S.; Foley, A.R.; Sailer, A.; Hurles, M.E.; Stalker, J.; Hargreaves, I.; et al. NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. Cell Rep. 2013, 3, 1795–1805.
  64. Tiranti, V.; Hoertnagel, K.; Carrozzo, R.; Galimberti, C.; Munaro, M.; Granatiero, M.; Zelante, L.; Gasparini, P.; Marzella, R.; Rocchi, M.; et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am. J. Hum. Genet. 1998, 63, 1609–1621.
  65. Zhu, Z.; Yao, J.; Johns, T.; Fu, K.; De Bie, I.; Macmillan, C.; Cuthbert, A.P.; Newbold, R.F.; Wang, J.; Chevrette, M.; et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat. Genet. 1998, 20, 337–343.
  66. Papadopoulou, L.C.; Sue, C.M.; Davidson, M.M.; Tanji, K.; Nishino, I.; Sadlock, J.E.; Krishna, S.; Walker, W.; Selby, J.; Glerum, D.M.; et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat. Genet. 1999, 23, 333–337.
  67. Valnot, I.; Osmond, S.; Gigarel, N.; Mehaye, B.; Amiel, J.; Cormier-Daire, V.; Munnich, A.; Bonnefont, J.P.; Rustin, P.; Rotig, A. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am. J. Hum. Genet. 2000, 67, 1104–1109.
  68. Antonicka, H.; Leary, S.C.; Guercin, G.H.; Agar, J.N.; Horvath, R.; Kennaway, N.G.; Harding, C.O.; Jaksch, M.; Shoubridge, E.A. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum. Mol. Genet. 2003, 12, 2693–2702.
  69. Antonicka, H.; Mattman, A.; Carlson, C.G.; Glerum, D.M.; Hoffbuhr, K.C.; Leary, S.C.; Kennaway, N.G.; Shoubridge, E.A. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am. J. Hum. Genet. 2003, 72, 101–114.
  70. Bugiani, M.; Tiranti, V.; Farina, L.; Uziel, G.; Zeviani, M. Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. J. Med. Genet. 2005, 42, e28.
  71. Weraarpachai, W.; Sasarman, F.; Nishimura, T.; Antonicka, H.; Aure, K.; Rotig, A.; Lombes, A.; Shoubridge, E.A. Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis. Am. J. Hum. Genet. 2012, 90, 142–151.
  72. Li, P.; Guo, D.; Zhang, X.; Ji, K.; Lv, H.; Zhang, Y.; Chen, Z.; Ma, J.; Fang, Y.; Liu, Y. Compound Heterozygous COX20 Variants Impair the Function of Mitochondrial Complex IV to Cause a Syndrome Involving Ophthalmoplegia and Visual Failure. Front. Neurol. 2022, 13, 873943.
  73. Ostergaard, E.; Weraarpachai, W.; Ravn, K.; Born, A.P.; Jonson, L.; Duno, M.; Wibrand, F.; Shoubridge, E.A.; Vissing, J. Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature. J. Med. Genet. 2015, 52, 203–207.
  74. Lim, S.C.; Smith, K.R.; Stroud, D.A.; Compton, A.G.; Tucker, E.J.; Dasvarma, A.; Gandolfo, L.C.; Marum, J.E.; McKenzie, M.; Peters, H.L.; et al. A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. Am. J. Hum. Genet. 2014, 94, 209–222.
  75. Renkema, G.H.; Visser, G.; Baertling, F.; Wintjes, L.T.; Wolters, V.M.; van Montfrans, J.; de Kort, G.A.P.; Nikkels, P.G.J.; van Hasselt, P.M.; van der Crabben, S.N.; et al. Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions. Hum. Genet. 2017, 136, 759–769.
  76. Huigsloot, M.; Nijtmans, L.G.; Szklarczyk, R.; Baars, M.J.; van den Brand, M.A.; Hendriksfranssen, M.G.; van den Heuvel, L.P.; Smeitink, J.A.; Huynen, M.A.; Rodenburg, R.J. A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy. Am. J. Hum. Genet. 2011, 88, 488–493.
  77. Baertling, F.; M, A.M.v.d.B.; Hertecant, J.L.; Al-Shamsi, A.; L, P.v.d.H.; Distelmaier, F.; Mayatepek, E.; Smeitink, J.A.; Nijtmans, L.G.; Rodenburg, R.J. Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy. Hum. Mutat. 2015, 36, 34–38.
  78. Martinez Lyons, A.; Ardissone, A.; Reyes, A.; Robinson, A.J.; Moroni, I.; Ghezzi, D.; Fernandez-Vizarra, E.; Zeviani, M. COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency. J. Med. Genet. 2016, 53, 846–849.
  79. Sharma, S.; Singh, P.; Fernandez-Vizarra, E.; Zeviani, M.; Van der Knaap, M.S.; Saran, R.K. Cavitating Leukoencephalopathy With Posterior Predominance Caused by a Deletion in the APOPT1 Gene in an Indian Boy. J. Child Neurol. 2018, 33, 428–431.
  80. Mootha, V.K.; Lepage, P.; Miller, K.; Bunkenborg, J.; Reich, M.; Hjerrild, M.; Delmonte, T.; Villeneuve, A.; Sladek, R.; Xu, F.; et al. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc. Natl. Acad. Sci. USA 2003, 100, 605–610.
  81. Yoo, D.H.; Choi, Y.C.; Nam, D.E.; Choi, S.S.; Kim, J.W.; Choi, B.O.; Chung, K.W. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome. Mitochondrion 2017, 35, 54–58.
  82. Weraarpachai, W.; Antonicka, H.; Sasarman, F.; Seeger, J.; Schrank, B.; Kolesar, J.E.; Lochmuller, H.; Chevrette, M.; Kaufman, B.A.; Horvath, R.; et al. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat. Genet. 2009, 41, 833–837.
  83. Brischigliaro, M.; Zeviani, M. Cytochrome c oxidase deficiency. Biochim. Biophys. Acta Bioenerg. 2021, 1862, 148335.
  84. Foltopoulou, P.F.; Zachariadis, G.A.; Politou, A.S.; Tsiftsoglou, A.S.; Papadopoulou, L.C. Human recombinant mutated forms of the mitochondrial COX assembly Sco2 protein differ from wild-type in physical state and copper binding capacity. Mol. Genet. Metab. 2004, 81, 225–236.
  85. Ghosh, A.; Pratt, A.T.; Soma, S.; Theriault, S.G.; Griffin, A.T.; Trivedi, P.P.; Gohil, V.M. Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 biogenesis. Hum. Mol. Genet. 2016, 25, 660–671.
  86. Jaksch, M.; Paret, C.; Stucka, R.; Horn, N.; Muller-Hocker, J.; Horvath, R.; Trepesch, N.; Stecker, G.; Freisinger, P.; Thirion, C.; et al. Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum. Mol. Genet. 2001, 10, 3025–3035.
  87. Leary, S.C.; Kaufman, B.A.; Pellecchia, G.; Guercin, G.H.; Mattman, A.; Jaksch, M.; Shoubridge, E.A. Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum. Mol. Genet. 2004, 13, 1839–1848.
  88. Pacheu-Grau, D.; Bareth, B.; Dudek, J.; Juris, L.; Vogtle, F.N.; Wissel, M.; Leary, S.C.; Dennerlein, S.; Rehling, P.; Deckers, M. Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies. Cell Metab. 2015, 21, 823–833.
  89. Soma, S.; Morgada, M.N.; Naik, M.T.; Boulet, A.; Roesler, A.A.; Dziuba, N.; Ghosh, A.; Yu, Q.; Lindahl, P.A.; Ames, J.B.; et al. COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase. Cell Rep. 2019, 29, 4114–4126 e4115.
  90. Leary, S.C.; Sasarman, F.; Nishimura, T.; Shoubridge, E.A. Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1. Hum. Mol. Genet. 2009, 18, 2230–2240.
  91. Williams, J.C.; Sue, C.; Banting, G.S.; Yang, H.; Glerum, D.M.; Hendrickson, W.A.; Schon, E.A. Crystal structure of human SCO1: Implications for redox signaling by a mitochondrial cytochrome c oxidase “assembly” protein. J. Biol. Chem. 2005, 280, 15202–15211.
  92. Assaily, W.; Benchimol, S. Differential utilization of two ATP-generating pathways is regulated by p53. Cancer Cell 2006, 10, 4–6.
  93. Matoba, S.; Kang, J.G.; Patino, W.D.; Wragg, A.; Boehm, M.; Gavrilova, O.; Hurley, P.J.; Bunz, F.; Hwang, P.M. p53 regulates mitochondrial respiration. Science 2006, 312, 1650–1653.
  94. Barcia, G.; Assouline, Z.; Pennisi, A.; Gitiaux, C.; Schiff, M.; Boddaert, N.; Munnich, A.; Bonnefont, J.P.; Rotig, A. Cytochrome c oxidase deficiency caused by biallelic SCO2 mutations in two sibs with cerebellar ataxia and progressive peripheral axonal neuropathy. Mol. Genet. Metab. Rep. 2019, 21, 100528.
  95. Gangfuss, A.; Hentschel, A.; Rademacher, N.; Sickmann, A.; Stuve, B.; Horvath, R.; Gross, C.; Kohlschmidt, N.; Forster, F.; Abicht, A.; et al. Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease. Hum. Mutat. 2022, 43, 477–486.
  96. Gurgel-Giannetti, J.; Oliveira, G.; Brasileiro Filho, G.; Martins, P.; Vainzof, M.; Hirano, M. Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: Case report and literature review. JAMA Neurol. 2013, 70, 258–261.
  97. Jaksch, M.; Ogilvie, I.; Yao, J.; Kortenhaus, G.; Bresser, H.G.; Gerbitz, K.D.; Shoubridge, E.A. Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum. Mol. Genet. 2000, 9, 795–801.
  98. Joost, K.; Rodenburg, R.; Piirsoo, A.; van den Heuvel, B.; Zordania, R.; Ounap, K. A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy. Pediatr. Neurol. 2010, 42, 227–230.
  99. Knuf, M.; Faber, J.; Huth, R.G.; Freisinger, P.; Zepp, F.; Kampmann, C. Identification of a novel compound heterozygote SCO2 mutation in cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy. Acta Paediatr. 2007, 96, 130–132.
  100. Leary, S.C.; Mattman, A.; Wai, T.; Koehn, D.C.; Clarke, L.A.; Chan, S.; Lomax, B.; Eydoux, P.; Vallance, H.D.; Shoubridge, E.A. A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy. Mol. Genet. Metab. 2006, 89, 129–133.
  101. Mobley, B.C.; Enns, G.M.; Wong, L.J.; Vogel, H. A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy. Clin. Neuropathol. 2009, 28, 143–149.
  102. Pronicka, E.; Piekutowska-Abramczuk, D.; Szymanska-Debinska, T.; Bielecka, L.; Kowalski, P.; Luczak, S.; Karkucinska-Wieckowska, A.; Migdal, M.; Kubalska, J.; Zimowski, J.; et al. The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation. Mitochondrion 2013, 13, 810–816.
  103. Pronicki, M.; Kowalski, P.; Piekutowska-Abramczuk, D.; Taybert, J.; Karkucinska-Wieckowska, A.; Szymanska-Debinska, T.; Karczmarewicz, E.; Pajdowska, M.; Migdal, M.; Milewska-Bobula, B.; et al. A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency. Eur. J. Paediatr. Neurol. 2010, 14, 253–260.
  104. Rebelo, A.P.; Saade, D.; Pereira, C.V.; Farooq, A.; Huff, T.C.; Abreu, L.; Moraes, C.T.; Mnatsakanova, D.; Mathews, K.; Yang, H.; et al. SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain 2018, 141, 662–672.
  105. Sacconi, S.; Salviati, L.; Sue, C.M.; Shanske, S.; Davidson, M.M.; Bonilla, E.; Naini, A.B.; De Vivo, D.C.; DiMauro, S. Mutation screening in patients with isolated cytochrome c oxidase deficiency. Pediatr. Res. 2003, 53, 224–230.
  106. Salviati, L.; Sacconi, S.; Rasalan, M.M.; Kronn, D.F.; Braun, A.; Canoll, P.; Davidson, M.; Shanske, S.; Bonilla, E.; Hays, A.P.; et al. Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. Arch. Neurol. 2002, 59, 862–865.
  107. Sambuughin, N.; Liu, X.; Bijarnia, S.; Wallace, T.; Verma, I.C.; Hamilton, S.; Muldoon, S.; Tallon, L.J.; Wang, S. Exome sequencing reveals SCO2 mutations in a family presented with fatal infantile hyperthermia. J. Hum. Genet. 2013, 58, 226–228.
  108. Szymanska-Debinska, T.; Karkucinska-Wieckowska, A.; Piekutowska-Abramczuk, D.; Jurkiewicz, E.; Iwanicka-Pronicka, K.; Rokicki, D.; Pronicki, M. Leigh disease due to SCO2 mutations revealed at extended autopsy. J. Clin. Pathol. 2015, 68, 397–399.
  109. Tarnopolsky, M.A.; Bourgeois, J.M.; Fu, M.H.; Kataeva, G.; Shah, J.; Simon, D.K.; Mahoney, D.; Johns, D.; MacKay, N.; Robinson, B.H. Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. Am. J. Med. Genet. A 2004, 125A, 310–314.
  110. Tay, S.K.; Shanske, S.; Kaplan, P.; DiMauro, S. Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch. Neurol 2004, 61, 950–952.
  111. Tran-Viet, K.N.; Powell, C.; Barathi, V.A.; Klemm, T.; Maurer-Stroh, S.; Limviphuvadh, V.; Soler, V.; Ho, C.; Yanovitch, T.; Schneider, G.; et al. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am. J. Hum. Genet. 2013, 92, 820–826.
  112. Verdijk, R.M.; de Krijger, R.; Schoonderwoerd, K.; Tiranti, V.; Smeets, H.; Govaerts, L.C.; de Coo, R. Phenotypic consequences of a novel SCO2 gene mutation. Am. J. Med. Genet. A 2008, 146A, 2822–2827.
  113. Vesela, K.; Hansikova, H.; Tesarova, M.; Martasek, P.; Elleder, M.; Houstek, J.; Zeman, J. Clinical, biochemical and molecular analyses of six patients with isolated cytochrome c oxidase deficiency due to mutations in the SCO2 gene. Acta Paediatr. 2004, 93, 1312–1317.
  114. Vesela, K.; Hulkova, H.; Hansikova, H.; Zeman, J.; Elleder, M. Structural analysis of tissues affected by cytochrome C oxidase deficiency due to mutations in the SCO2 gene. APMIS 2008, 116, 41–49.
  115. Vondrackova, A.; Vesela, K.; Kratochvilova, H.; Kucerova Vidrova, V.; Vinsova, K.; Stranecky, V.; Honzik, T.; Hansikova, H.; Zeman, J.; Tesarova, M. Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders. Eur. J. Hum. Genet. 2014, 22, 431–434.
  116. Rucheton, B.; Ewenczyk, C.; Gaignard, P.; de Sainte Agathe, J.M.; Fauret, A.L.; Saillour, V.; Leonard-Louis, S.; Touitou, V.; Mochel, F. Adult Cerebellar Ataxia, Axonal Neuropathy, and Sensory Impairments Caused by Biallelic SCO2 Variants. Neurol. Genet. 2021, 7, e630.
  117. Wakazono, T.; Miyake, M.; Yamashiro, K.; Yoshikawa, M.; Yoshimura, N. Association between SCO2 mutation and extreme myopia in Japanese patients. Jpn. J. Ophthalmol. 2016, 60, 319–325.
  118. Bohm, M.; Pronicka, E.; Karczmarewicz, E.; Pronicki, M.; Piekutowska-Abramczuk, D.; Sykut-Cegielska, J.; Mierzewska, H.; Hansikova, H.; Vesela, K.; Tesarova, M.; et al. Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency. Pediatr. Res. 2006, 59, 21–26.
  119. Jiang, D.; Li, J.; Xiao, X.; Li, S.; Jia, X.; Sun, W.; Guo, X.; Zhang, Q. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Investig. Ophthalmol. Vis. Sci. 2014, 56, 339–345.
  120. Cai, X.B.; Zheng, Y.H.; Chen, D.F.; Zhou, F.Y.; Xia, L.Q.; Wen, X.R.; Yuan, Y.M.; Han, F.; Piao, S.Y.; Zhuang, W.; et al. Expanding the Phenotypic and Genotypic Landscape of Nonsyndromic High Myopia: A Cross-Sectional Study in 731 Chinese Patients. Investig. Ophthalmol. Vis. Sci. 2019, 60, 4052–4062.
  121. Zheng, Y.H.; Cai, X.B.; Xia, L.Q.; Zhou, F.Y.; Wen, X.R.; Chen, D.F.; Han, F.; Zhou, K.J.; Jin, Z.B.; Zhuang, W.J.; et al. Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia. Mol. Vis. 2021, 27, 706–717.
  122. Jaksch, M.; Horvath, R.; Horn, N.; Auer, D.P.; Macmillan, C.; Peters, J.; Gerbitz, K.D.; Kraegeloh-Mann, I.; Muntau, A.; Karcagi, V.; et al. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 2001, 57, 1440–1446.
  123. Yang, H.; Brosel, S.; Acin-Perez, R.; Slavkovich, V.; Nishino, I.; Khan, R.; Goldberg, I.J.; Graziano, J.; Manfredi, G.; Schon, E.A. Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2. Hum. Mol. Genet. 2010, 19, 170–180.
  124. Hill, S.; Deepa, S.S.; Sataranatarajan, K.; Premkumar, P.; Pulliam, D.; Liu, Y.; Soto, V.Y.; Fischer, K.E.; Van Remmen, H. Sco2 deficient mice develop increased adiposity and insulin resistance. Mol. Cell. Endocrinol. 2017, 455, 103–114.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Parthena F. Foltopoulou
,
Androulla N. Miliotou
,
Alexandra Ingendoh-Tsakmakidis
,
Asterios S. Tsiftsoglou
,
Ioannis S. Vizirianakis
,
Ioannis S. Pappas
,
Lefkothea C. Papadopoulou
View Times: 458
Entry Collection: Neurodegeneration
Revisions: 5 times (View History)
Update Date: 28 Jan 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback