Mutations in the UQCC1-Interacting Protein, UQCC2, Cause Human Complex III Deficiency Associated with Perturbed Cytochrome Protein Expression

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Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for generating the majority of cellular ATP. Complex III (ubiquinol-cytochrome c oxidoreductase) is the third of five OXPHOS complexes. Complex III assembly relies on the coordinated expression of the mitochondrial and nuclear genomes, with 10 subunits encoded by nuclear DNA and one by mitochondrial DNA (mtDNA). Complex III deficiency is a debilitating and often fatal disorder that can arise from mutations in complex III subunit genes or one of three known complex III assembly factors. The molecular cause for complex III deficiency in about half of cases, however, is unknown and there are likely many complex III assembly factors yet to be identified. Here, we used Massively Parallel Sequencing to identify a homozygous splicing mutation in the gene encoding Ubiquinol-Cytochrome c Reductase Complex Assembly Factor 2 (UQCC2) in a consanguineous Lebanese patient displaying complex III deficiency, severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction. We prove causality of the mutation via lentiviral correction studies in patient fibroblasts. Sequence-profile based orthology prediction shows UQCC2 is an ortholog of the Saccharomyces cerevisiae complex III assembly factor, Cbp6p, although its sequence has diverged substantially. Co-purification studies show that UQCC2 interacts with UQCC1, the predicted ortholog of the Cbp6p binding partner, Cbp3p. Fibroblasts from the patient with UQCC2 mutations have deficiency of UQCC1, while UQCC1-depleted cells have reduced levels of UQCC2 and complex III. We show that UQCC1 binds the newly synthesized mtDNA-encoded cytochrome b subunit of complex III and that UQCC2 patient fibroblasts have specific defects in the synthesis or stability of cytochrome b. This work reveals a new cause for complex III deficiency that can assist future patient diagnosis, and provides insight into human complex III assembly by establishing that UQCC1 and UQCC2 are complex III assembly factors participating in cytochrome b biogenesis.

Vyšlo v časopise: Mutations in the UQCC1-Interacting Protein, UQCC2, Cause Human Complex III Deficiency Associated with Perturbed Cytochrome Protein Expression. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1004034
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004034

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1. SkladalD, HallidayJ, ThorburnDR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126: 1905–1912.

2. MeunierB, FisherN, RansacS, MazatJP, BrasseurG (2012) Respiratory complex III dysfunction in humans and the use of yeast as a model organism to study mitochondrial myopathy and associated diseases. Biochim Biophys Acta 1827: 1346–61.

3. DumoulinR, SagnolI, FerlinT, BozonD, StepienG, et al. (1996) A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance. Mol Cell Probes 10: 389–391.

4. FisherN, MeunierB (2001) Effects of mutations in mitochondrial cytochrome b in yeast and man. Deficiency, compensation and disease. Eur J Biochem 268: 1155–1162.

5. HautS, BrivetM, TouatiG, RustinP, LebonS, et al. (2003) A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis. Hum Genet 113: 118–122.

6. BarelO, ShorerZ, FlusserH, OfirR, NarkisG, et al. (2008) Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet 82: 1211–1216.

7. MiyakeN, YanoS, SakaiC, HatakeyamaH, MatsushimaY, et al. (2012) Mitochondrial Complex III Deficiency Caused by a Homozygous UQCRC2 Mutation Presenting with Neonatal-Onset Recurrent Metabolic Decompensation. Hum Mutat 34: 446–452.

8. GaignardP, MenezesM, SchiffM, BayotA, RakM, et al. (2013) Mutations in the cytochrome c1 subunit of respiratory chain complex III cause insulin-responsive hyperglycemia. Am J Hum Genet 93 (2) 384–9.

9. de LonlayP, ValnotI, BarrientosA, GorbatyukM, TzagoloffA, et al. (2001) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 29: 57–60.

10. GhezziD, ArzuffiP, ZordanM, Da ReC, LampertiC, et al. (2011) Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet 43: 259–263.

11. InvernizziF, TiganoM, DallabonaC, DonniniC, FerreroI, et al. (2013) A homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis and Severe Reduction of Mitochondrial Complex III Activity. Hum Mutat 34 (12) 1619–22.

12. KotarskyH, KarikoskiR, MorgelinM, MarjavaaraS, BergmanP, et al. (2010) Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation. Mitochondrion 10: 497–509.

13. Fernandez-VizarraE, BugianiM, GoffriniP, CarraraF, FarinaL, et al. (2007) Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum Mol Genet 16: 1241–1252.

14. HinsonJT, FantinVR, SchonbergerJ, BreivikN, SiemG, et al. (2007) Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. N Engl J Med 356: 809–819.

15. NogueiraC, BarrosJ, SaMJ, AzevedoL, TaipaR, et al. (2013) Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency. Neurogenetics 14: 153–160.

16. LamanteaE, CarraraF, MariottiC, MorandiL, TirantiV, et al. (2002) A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III. Neuromuscul Disord 12: 49–52.

17. Acin-PerezR, Bayona-BafaluyMP, Fernandez-SilvaP, Moreno-LoshuertosR, Perez-MartosA, et al. (2004) Respiratory complex III is required to maintain complex I in mammalian mitochondria. Mol Cell 13: 805–815.

18. BrunoC, SantorelliFM, AsseretoS, TonoliE, TessaA, et al. (2003) Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene. Muscle Nerve 28: 508–511.

19. DiazF, EnriquezJA, MoraesCT (2012) Cells lacking Rieske iron-sulfur protein have a reactive oxygen species-associated decrease in respiratory complexes I and IV. Mol Cell Biol 32: 415–429.

20. CalvoSE, ComptonAG, HershmanSG, LimSC, LieberDS, et al. (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 4: 118ra110.

21. SherryST, WardMH, KholodovM, BakerJ, PhanL, et al. (2001) dbSNP: the NCBI database of genetic variation. Nucleic acids research 29: 308–311.

22. DurbinRM, AbecasisGR, AltshulerDL, AutonA, BrooksLD, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

23. HiranoM, Lagier-TourenneC, ValentinoML, MartiR, NishigakiY (2005) Thymidine phosphorylase mutations cause instability of mitochondrial DNA. Gene 354: 152–156.

24. McManusCJ, GraveleyBR (2011) RNA structure and the mechanisms of alternative splicing. Curr Opin Genet Dev 21: 373–379.

25. SumitaniM, KasashimaK, OhtaE, KangD, EndoH (2009) Association of a novel mitochondrial protein M19 with mitochondrial nucleoids. J Biochem 146: 725–732.

26. SzklarczykR, WanschersBF, CuypersTD, EsselingJJ, RiemersmaM, et al. (2012) Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase. Genome biology 13: R12.

27. DieckmannCL, TzagoloffA (1985) Assembly of the mitochondrial membrane system. CBP6, a yeast nuclear gene necessary for synthesis of cytochrome b. J Biol Chem 260: 1513–1520.

28. ShiG, CrivelloneMD, EdderkaouiB (2001) Identification of functional regions of Cbp3p, an enzyme-specific chaperone required for the assembly of ubiquinol-cytochrome c reductase in yeast mitochondria. Biochim Biophys Acta 1506: 103–116.

29. GruschkeS, KehreinK, RomplerK, GroneK, IsraelL, et al. (2011) Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly. J Cell Biol 193: 1101–1114.

30. GruschkeS, RomplerK, HildenbeutelM, KehreinK, KuhlI, et al. (2012) The Cbp3–Cbp6 complex coordinates cytochrome b synthesis with bc(1) complex assembly in yeast mitochondria. J Cell Biol 199: 137–150.

31. PagliariniDJ, CalvoSE, ChangB, ShethSA, VafaiSB, et al. (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134: 112–123.

32. TuckerEJ, HershmanSG, KohrerC, Belcher-TimmeCA, PatelJ, et al. (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab 14: 428–434.

33. LimSC, FriemelM, MarumJE, TuckerEJ, BrunoDL, et al. (2013) Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Hum Mol Genet 22 (22) 4460–73.

34. CambierL, RassamP, ChabiB, MezghennaK, GrossR, et al. (2012) M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic beta-cells through modulation of respiratory chain activity. PLoS One 7: e31815.

35. SoranzoN, RivadeneiraF, Chinappen-HorsleyU, MalkinaI, RichardsJB, et al. (2009) Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size. PLoS Genet 5: e1000445.

36. DengFY, DongSS, XuXH, LiuYJ, LiuYZ, et al. (2013) Genome-wide association study identified UQCC locus for spine bone size in humans. Bone 53: 129–133.

37. SannaS, JacksonAU, NagarajaR, WillerCJ, ChenWM, et al. (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40: 198–203.

38. HeJ, CooperHM, ReyesA, Di ReM, SembongiH, et al. (2012) Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis. Nucleic acids research 40: 6109–6121.

39. KuhlI, FoxTD, BonnefoyN (2012) Schizosaccharomyces pombe homologs of the Saccharomyces cerevisiae mitochondrial proteins Cbp6 and Mss51 function at a post-translational step of respiratory complex biogenesis. Mitochondrion 12: 381–390.

40. WeraarpachaiW, AntonickaH, SasarmanF, SeegerJ, SchrankB, et al. (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nature Genetics 41: 833–837.

41. CalvoSE, TuckerEJ, ComptonAG, KirbyDM, CrawfordG, et al. (2010) High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 42: 851–858.

42. AshleyN, HarrisD, PoultonJ (2005) Detection of mitochondrial DNA depletion in living human cells using PicoGreen staining. Exp Cell Res 303: 432–446.

43. KirbyDM, CrawfordM, ClearyMA, DahlHH, DennettX, et al. (1999) Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology 52: 1255–1264.

44. RodenburgRJ (2011) Biochemical diagnosis of mitochondrial disorders. Journal of inherited metabolic disease 34: 283–292.

45. DenoeudF, RousselM, NoelB, WawrzyniakI, Da SilvaC, et al. (2011) Genome sequence of the stramenopile Blastocystis, a human anaerobic parasite. Genome biology 12: R29.

46. AltschulSF, MaddenTL, SchafferAA, ZhangJ, ZhangZ, et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic acids research 25: 3389–3402.

47. LattinJE, SchroderK, SuAI, WalkerJR, ZhangJ, et al. (2008) Expression analysis of G Protein-Coupled Receptors in mouse macrophages. Immunome research 4: 5.

48. SzklarczykR, WanschersBF, NijtmansLG, RodenburgRJ, ZschockeJ, et al. (2013) A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. Human molecular genetics 22: 656–667.

49. TuckerEJ, MimakiM, ComptonAG, McKenzieM, RyanMT, et al. (2012) Next-generation sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. Hum Mutat 33: 411–418.

50. HeL, ChinneryPF, DurhamSE, BlakelyEL, WardellTM, et al. (2002) Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic acids research 30: e68.

51. PagnamentaAT, TaanmanJW, WilsonCJ, AndersonNE, MarottaR, et al. (2006) Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 21: 2467–2473.

52. BrunoDL, StarkZ, AmorDJ, BurgessT, ButlerK, et al. (2011) Extending the scope of diagnostic chromosome analysis: detection of single gene defects using high-resolution SNP microarrays. Hum Mutat 32: 1500–1506.

53. YeapYY, NgIH, BadrianB, NguyenTV, YipYY, et al. (2010) c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18. Biochem J 430: 345–354.

54. CalvarusoMA, SmeitinkJ, NijtmansL (2008) Electrophoresis techniques to investigate defects in oxidative phosphorylation. Methods 46: 281–287.

55. McKenzieM, LazarouM, ThorburnDR, RyanMT (2007) Analysis of mitochondrial subunit assembly into respiratory chain complexes using Blue Native polyacrylamide gel electrophoresis. Anal Biochem 364: 128–137.

56. ProcaccioV, MoussonB, BeugnotR, DuborjalH, FeilletF, et al. (1999) Nuclear DNA origin of mitochondrial complex I deficiency in fatal infantile lactic acidosis evidenced by transnuclear complementation of cultured fibroblasts. J Clin Invest 104: 83–92.

57. SistermansEA, de KokYJ, PetersW, GinselLA, JapPH, et al. (1995) Tissue- and cell-specific distribution of creatine kinase B: a new and highly specific monoclonal antibody for use in immunohistochemistry. Cell Tissue Res 280: 435–446.

58. McKenzieM, LazarouM, RyanMT (2009) Chapter 18 Analysis of respiratory chain complex assembly with radiolabeled nuclear- and mitochondrial-encoded subunits. Methods Enzymol 456: 321–339.

59. BouletL, KarpatiG, ShoubridgeEA (1992) Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 51: 1187–1200.

60. BechtelS, RosenfelderH, DudaA, SchmidtCP, ErnstU, et al. (2007) The full-ORF clone resource of the German cDNA Consortium. BMC Genomics 8: 399.

61. YuanB, LatekR, HossbachM, TuschlT, LewitterF (2004) siRNA Selection Server: an automated siRNA oligonucleotide prediction server. Nucleic acids research 32: W130–134.

62. VogelRO, JanssenRJ, UgaldeC, GrovensteinM, HuijbensRJ, et al. (2005) Human mitochondrial complex I assembly is mediated by NDUFAF1. FEBS J 272: 5317–5326.

63. DuxinJP, DaoB, MartinssonP, RajalaN, GuittatL, et al. (2009) Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol Cell Biol 29: 4274–4282.

64. UgaldeC, VogelR, HuijbensR, Van Den HeuvelB, SmeitinkJ, et al. (2004) Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies. Human molecular genetics 13: 2461–2472.

65. WaterhouseAM, ProcterJB, MartinDM, ClampM, BartonGJ (2009) Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics 25: 1189–1191.

66. FinnRD, TateJ, MistryJ, CoggillPC, SammutSJ, et al. (2008) The Pfam protein families database. Nucleic Acids Res 36: D281–288.

67. Fernandez-VizarraE, TirantiV, ZevianiM (2009) Assembly of the oxidative phosphorylation system in humans: what we have learned by studying its defects. Biochim Biophys Acta 1793: 200–211.