A salvage pathway maintains highly functional respiratory complex I.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 04 2020
02 04 2020
Historique:
received:
09
08
2019
accepted:
05
03
2020
entrez:
4
4
2020
pubmed:
4
4
2020
medline:
25
7
2020
Statut:
epublish
Résumé
Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation of dysfunctional CI arising from the inactivation of the N-module subunits due to attrition caused by its constant activity under physiological conditions. This CI salvage pathway maintains highly functional CI through a favorable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. Our results also identify ClpXP activity as an unforeseen target for therapeutic interventions in the large group of mitochondrial diseases characterized by the CI instability.
Identifiants
pubmed: 32242014
doi: 10.1038/s41467-020-15467-7
pii: 10.1038/s41467-020-15467-7
pmc: PMC7118099
doi:
Substances chimiques
Protein Subunits
0
CLPP protein, mouse
EC 3.4.21.92
Endopeptidase Clp
EC 3.4.21.92
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1643Références
Brandt, U. Energy converting NADH:quinone oxidoreductase (complex I). Annu. Rev. Biochem. 75, 69–92 (2006).
doi: 10.1146/annurev.biochem.75.103004.142539
Hirst, J. Mitochondrial complex I. Annu. Rev. Biochem. 82, 551–575 (2013).
doi: 10.1146/annurev-biochem-070511-103700
Fiedorczuk, K. & Sazanov, L. A. Mammalian mitochondrial complex I structure and disease-causing mutations. Trends Cell Biol. 28, 835–867 (2018).
doi: 10.1016/j.tcb.2018.06.006
Urra, F. A., Munoz, F., Lovy, A. & Cardenas, C. The mitochondrial complex(I)ty of cancer. Front. Oncol. 7, 118 (2017).
doi: 10.3389/fonc.2017.00118
pubmed: 5462917
pmcid: 5462917
Stefanatos, R. & Sanz, A. Mitochondrial complex I: a central regulator of the aging process. Cell Cycle 10, 1528–1532 (2011).
doi: 10.4161/cc.10.10.15496
Zhu, J., Vinothkumar, K. R. & Hirst, J. Structure of mammalian respiratory complex I. Nature 536, 354–358 (2016).
doi: 10.1038/nature19095
pubmed: 5027920
pmcid: 5027920
Fiedorczuk, K. et al. Atomic structure of the entire mammalian mitochondrial complex I. Nature 538, 406–410 (2016).
doi: 10.1038/nature19794
pubmed: 5164932
pmcid: 5164932
Stroud, D. A. et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538, 123–126 (2016).
doi: 10.1038/nature19754
Guerrero-Castillo, S. et al. The assembly pathway of mitochondrial respiratory chain complex I. Cell Metab. 25, 128–139 (2017).
doi: 10.1016/j.cmet.2016.09.002
Drose, S. & Brandt, U. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv. Exp. Med. Biol. 748, 145–169 (2012).
doi: 10.1007/978-1-4614-3573-0_6
pubmed: 22729857
pmcid: 22729857
Hirst, J. & Roessler, M. M. Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I. Biochim. et. Biophys. Acta (BBA)-Bioenerg. 1857, 872–883 (2016).
doi: 10.1016/j.bbabio.2015.12.009
Chouchani, E. T. et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med. 19, 753–759 (2013).
doi: 10.1038/nm.3212
pubmed: 23708290
pmcid: 23708290
Schagger, H. et al. Significance of respirasomes for the assembly/stability of human respiratory chain complex I. J. Biol. Chem. 279, 36349–36353 (2004).
doi: 10.1074/jbc.M404033200
pubmed: 15208329
pmcid: 15208329
Lapuente-Brun, E. et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 340, 1567–1570 (2013).
doi: 10.1126/science.1230381
pubmed: 23812712
pmcid: 23812712
Guaras, A. et al. The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency. Cell Rep. 15, 197–209 (2016).
doi: 10.1016/j.celrep.2016.03.009
pubmed: 27052170
pmcid: 27052170
Zurita Rendon, O. & Shoubridge, E. A. Early complex I assembly defects result in rapid turnover of the ND1 subunit. Hum. Mol. Genet. 21, 3815–3824 (2012).
doi: 10.1093/hmg/dds209
pubmed: 22653752
pmcid: 22653752
Hornig-Do, H. T. et al. Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly. EMBO J. 31, 1293–1307 (2012).
doi: 10.1038/emboj.2011.477
pubmed: 22252130
pmcid: 22252130
Szczepanowska, K. et al. CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels. EMBO J. 35, 2566–2583 (2016).
doi: 10.15252/embj.201694253
pubmed: 27797820
pmcid: 27797820
Baker, T. A. & Sauer, R. T. ClpXP, an ATP-powered unfolding and protein-degradation machine. Biochim. Biophys. Acta 1823, 15–28 (2012).
doi: 10.1016/j.bbamcr.2011.06.007
pubmed: 21736903
pmcid: 21736903
Maly, T., Zwicker, K., Cernescu, A., Brandt, U. & Prisner, T. F. New pulsed EPR methods and their application to characterize mitochondrial complex I. Biochim. Biophys. Acta 1787, 584–592 (2009).
doi: 10.1016/j.bbabio.2009.02.003
pubmed: 19366602
pmcid: 19366602
Li, Y. et al. An assembled complex IV maintains the stability and activity of complex I in mammalian mitochondria. J. Biol. Chem. 282, 17557–17562 (2007).
doi: 10.1074/jbc.M701056200
pubmed: 17452320
pmcid: 17452320
Seiferling, D. et al. Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt. EMBO Rep. 17, 953–964 (2016).
Hurd, T. R. et al. Complex I within oxidatively stressed bovine heart mitochondria is glutathionylated on Cys-531 and Cys-704 of the 75-kDa subunit: potential role of CYS residues in decreasing oxidative damage. J. Biol. Chem. 283, 24801–24815 (2008).
doi: 10.1074/jbc.M803432200
pubmed: 18611857
pmcid: 18611857
Stepanova, A. et al. Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury. Antioxid. Redox Signal. 31, 608–622 (2019).
doi: 10.1089/ars.2018.7693
pubmed: 31037949
pmcid: 31037949
Robb, E. L. et al. Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat. Free Radic. Biol. Med. 89, 883–894 (2015).
doi: 10.1016/j.freeradbiomed.2015.08.021
pubmed: 26454075
pmcid: 26454075
Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009).
doi: 10.1042/BJ20081386
pubmed: 19061483
pmcid: 19061483
Vinogradov, A. D. & Grivennikova, V. G. Oxidation of NADH and ROS production by respiratory complex I. Biochim. Biophys. Acta 1857, 863–871 (2016).
doi: 10.1016/j.bbabio.2015.11.004
pubmed: 26571336
pmcid: 26571336
Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 17993–17998 (2005).
doi: 10.1073/pnas.0508886102
pubmed: 16332961
pmcid: 16332961
Edgar, D. et al. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab. 10, 131–138 (2009).
doi: 10.1016/j.cmet.2009.06.010
pubmed: 19656491
pmcid: 19656491
Acin-Perez, R. et al. Respiratory complex III is required to maintain complex I in mammalian mitochondria. Mol. Cell 13, 805–815 (2004).
doi: 10.1016/S1097-2765(04)00124-8
pubmed: 3164363
pmcid: 3164363
Diaz, F., Fukui, H., Garcia, S. & Moraes, C. T. Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol. Cell Biol. 26, 4872–4881 (2006).
doi: 10.1128/MCB.01767-05
pubmed: 1489173
pmcid: 1489173
Kayser, E. B., Morgan, P. G., Hoppel, C. L. & Sedensky, M. M. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans. J. Biol. Chem. 276, 20551–20558 (2001).
doi: 10.1074/jbc.M011066200
Dogan, S. A. et al. Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart. Cell Metab. 19, 458–469 (2014).
doi: 10.1016/j.cmet.2014.02.004
Camara, Y. et al. MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome. Cell Metab. 13, 527–539 (2011).
doi: 10.1016/j.cmet.2011.04.002
Metodiev, M. D. et al. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. Cell Metab. 9, 386–397 (2009).
doi: 10.1016/j.cmet.2009.03.001
pubmed: 19356719
pmcid: 19356719
Agip A. A., Blaza J. N., Fedor J. G., & Hirst J. Mammalian respiratory complex I through the lens of cryo-EM. Annu. Rev. Biophys. 48, 165–184 (2019).
Kmita, K. et al. Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I. Proc. Natl Acad. Sci. USA 112, 5685–5690 (2015).
doi: 10.1073/pnas.1424353112
Stepanova, A. et al. Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury. Antioxid. Redox Signal. 31, 608–622 (2019).
Chen, J. et al. Peptide-based antibodies against glutathione-binding domains suppress superoxide production mediated by mitochondrial complex I. J. Biol. Chem. 285, 3168–3180 (2010).
doi: 10.1074/jbc.M109.056846
pubmed: 19940158
pmcid: 19940158
Chen, Y. R., Chen, C. L., Zhang, L., Green-Church, K. B. & Zweier, J. L. Superoxide generation from mitochondrial NADH dehydrogenase induces self-inactivation with specific protein radical formation. J. Biol. Chem. 280, 37339–37348 (2005).
doi: 10.1074/jbc.M503936200
pubmed: 16150735
pmcid: 16150735
Silva, P. et al. FtsH is involved in the early stages of repair of photosystem II in Synechocystis sp PCC 6803. Plant Cell 15, 2152–2164 (2003).
doi: 10.1105/tpc.012609
pubmed: 12953117
pmcid: 12953117
Kato, Y., Miura, E., Ido, K., Ifuku, K. & Sakamoto, W. The variegated mutants lacking chloroplastic FtsHs are defective in D1 degradation and accumulate reactive oxygen species. Plant Physiol. 151, 1790–1801 (2009).
doi: 10.1104/pp.109.146589
pubmed: 2785964
pmcid: 2785964
Nixon, P. J., Michoux, F., Yu, J., Boehm, M. & Komenda, J. Recent advances in understanding the assembly and repair of photosystem II. Ann. Bot. 106, 1–16 (2010).
doi: 10.1093/aob/mcq059
pubmed: 2889791
pmcid: 2889791
Arlt, H. et al. The formation of respiratory chain complexes in mitochondria is under the proteolytic control of the m-AAA protease. EMBO J. 17, 4837–4847 (1998).
doi: 10.1093/emboj/17.16.4837
pubmed: 1170813
pmcid: 1170813
Stiburek, L. et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol. Biol. Cell 23, 1010–1023 (2012).
doi: 10.1091/mbc.e11-08-0674
pubmed: 3302729
pmcid: 3302729
Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, RESEARCH0002 (2001).
doi: 10.1186/gb-2001-2-2-reports0002
Tyanova, S., Mann, M. & Cox, J. MaxQuant for in-depth analysis of large SILAC datasets. Methods Mol. Biol. 1188, 351–364 (2014).
doi: 10.1007/978-1-4939-1142-4_24
Madian, A. G. & Regnier, F. E. Proteomic identification of carbonylated proteins and their oxidation sites. J. Proteome Res. 9, 3766–3780 (2010).
doi: 10.1021/pr1002609
pubmed: 3214645
pmcid: 3214645
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
doi: 10.1038/nprot.2007.261
Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
doi: 10.1038/nbt.1511
pubmed: 19029910
pmcid: 19029910
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
doi: 10.1038/nmeth.3901
pubmed: 27348712
pmcid: 27348712
Fricker, M. D. Quantitative Redox Imaging Software. Antioxid. Redox Signal. 24, 752–762 (2016).
doi: 10.1089/ars.2015.6390
pubmed: 26154420
pmcid: 26154420
Faeder, E. J., Davis, P. S. & Siegel, L. M. Reduced nicotinamide adenine dinucleotide phosphate-sulfite reductase of enterobacteria. V. Studies with the Escherichia coli hemoflavoprotein depleted of flavin mononucleotide: distinct roles for the flavin adenine dinucleotide and flavin mononucleotide prosthetic groups in catalysis. J. Biol. Chem. 249, 1599–1609 (1974).
pubmed: 4150392
pmcid: 4150392