Abstract
Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the mitochondrial respiratory chain and is composed of 45 subunits in humans, making it one of the largest known multi-subunit membrane protein complexes1. Complex I exists in supercomplex forms with respiratory chain complexes III and IV, which are together required for the generation of a transmembrane proton gradient used for the synthesis of ATP2. Complex I is also a major source of damaging reactive oxygen species and its dysfunction is associated with mitochondrial disease, Parkinson’s disease and ageing3,4,5. Bacterial and human complex I share 14 core subunits that are essential for enzymatic function; however, the role and necessity of the remaining 31 human accessory subunits is unclear1,6. The incorporation of accessory subunits into the complex increases the cellular energetic cost and has necessitated the involvement of numerous assembly factors for complex I biogenesis. Here we use gene editing to generate human knockout cell lines for each accessory subunit. We show that 25 subunits are strictly required for assembly of a functional complex and 1 subunit is essential for cell viability. Quantitative proteomic analysis of cell lines revealed that loss of each subunit affects the stability of other subunits residing in the same structural module. Analysis of proteomic changes after the loss of specific modules revealed that ATP5SL and DMAC1 are required for assembly of the distal portion of the complex I membrane arm. Our results demonstrate the broad importance of accessory subunits in the structure and function of human complex I. Coupling gene-editing technology with proteomics represents a powerful tool for dissecting large multi-subunit complexes and enables the study of complex dysfunction at a cellular level.
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Acknowledgements
We thank M. Curtis, P. Faou, M. Lazarou, B. Porebski, L. Twigg, R. Schittenhelm (Monash Biomedical Proteomics Platform), A. Barugahare and P. Harrison (Monash Bioinformatics Platform), Monash Micro Imaging and the Micromon NGS Facility for assistance. We acknowledge funding from NHMRC Project Grants (1068056, 1107094) and fellowships (1070916 to D.A.S., 541920 to A.E.F., 1022896 to D.R.T.), the Australian Mitochondrial Disease Foundation and the Victorian Government’s Operational Infrastructure Support Program.
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D.A.S. and M.T.R. conceived the project and wrote the manuscript; D.A.S., D.R.T. and M.T.R. designed the experiments; D.A.S., E.E.S., L.E.F., B.R., M.G.D., L.D.O. and M.T.R. generated and analysed knockout lines; D.A.S. performed proteomic experiments; A.E.F. and T.S. performed enzymology; T.H.B. undertook transcript analysis; A.S. developed normalization algorithms.
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Reviewer Information Nature thanks J. Hirst, B. Lightowlers and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Extended Data Figure 1 Assembly analysis of the complex I/III/IV supercomplex in knockout cell lines.
Mitochondria were solubilized in digitonin and complexes separated by BN–PAGE followed by immunoblotting using the indicated antibodies. An antibody against complex V (CV) subunit ATP5A was used as loading control. #, subcomplexes; *, non-specific. SC, supercomplex.
Extended Data Figure 2 Steady-state levels of respiratory chain complexes I–IV and supercomplex forms in the 28 complex I accessory subunit knockout lines generated in this study.
NDUFA9KO has been analysed previously20, whereas the NDUFAB1KO is described in Extended Data Fig. 3. Mitochondria were solubilized in Triton X-100 (TX100) or digitonin (DIG) and analysed by BN–PAGE and immunoblotting with antibodies against NDUFA9 (complex I), SDHA (complex II), UQCRC1 (complex III) and COX4 (complex IV). In Triton X-100 samples, some complex III–IV supercomplex is retained. #, secondary clone later identified be an incomplete knockout.
Extended Data Figure 3 Generation and analysis of NDUFAB1-knockout cell lines.
a, Scheme detailing knockout strategy of genomic NDUFAB1 using doxycycline (DOX)-inducible expression of CRISPR/Cas9-resistant NDUFAB1 (NDUFAB1*Flag) or yACP1Flag. b, NDUFAB1 knockouts complemented with NDUFAB1Flag (NDUFAB1*-2) cells were cultured in media lacking DOX for the indicated times. Isolated mitochondria were analysed by BN–PAGE (Triton X-100) or SDS–PAGE and immunoblotting with the indicated antibodies. c, Brightfield images of cells grown ± DOX, or +DOX in glucose or galactose cell culture medium. Scale bars, 25 μm. Representative results from 4 independent experiments. d, SILAC-labelled mitochondria from DOX-treated HEK293T or NDUFAB1Flag (NDUFAB1*-2) cells were solubilized in Triton X-100 and incubated with anti-Flag affinity gel. Elutions were mixed and analysed by liquid chromatography–mass spectrometry (LC–MS). Proteins enriched with NDUFAB1 include complex I subunits and LYRM proteins. P values are from an unpaired single-sided t-test. n = 3 biological replicates; light grey dots, not significant (P >0.05). e, Mitochondria isolated from NDUFAB1 knockouts complemented with yACP1Flag or NDUFAB1Flag were solubilized in Triton X-100 and analysed by BN–PAGE and immunoblotting with the indicated antibodies.
Extended Data Figure 4 Analysis of N-module accessory subunits.
a, Mitochondria were isolated from cell lines, solubilized in Triton X-100 and analysed by BN–PAGE and immunoblotting for N-module subunit NDUFV1 or non N-module subunit NDUFA9. ‡, complex lacking N-module; N*, subcomplex containing N-module. SDHA was used as a loading control. b, Mitochondria were solubilized in digitonin and analysed by BN–PAGE and immunoblotting for NDUFAF2. †, NDUFAF2 associated complex I. c, [35S]methionine-labelled proteins were imported into the indicated mitochondria, solubilized in digitonin and analysed by BN–PAGE and autoradiography. 10% of the input lysate was analysed by SDS–PAGE and autoradiography. CISC, complex I supercomplex; *, non-specific band. d, Mitochondria isolated from NDUFV3-knockout cells complemented with NDUFV3Flag were solubilized in Triton X-100 or digitonin and complexes bound to anti-Flag affinity gel. Eluted proteins were analysed by LC–MS. P values are from an unpaired single-sided t-test. n = 3 biological replicates; light grey dots, not significant (P > 0.05).
Extended Data Figure 5 Proteomic analysis of knockout cell lines.
a, Relative levels of proteins in representative accessory subunit knockout cell lines, clustered according to Euclidean distance. Column order is as in Fig. 2b. The inset shows complex I subunit-specific clusters. b, Volcano plot depicting proteins regulated in representative accessory subunit knockout cell lines containing respiration defects (NDUFA2, NDUFA8, NDUFS5, NDUFC1, NDUFB10, NDUFB11 and NDUFB7 knockouts). Proteins found to be regulated in a cell line with a severe complex IV defect15 are shaded light blue (down) and green (up), suggesting their response is due to general defects in respiration. Inset, volcano plot depicting the relative level of proteins in a complex IV knockout cell line. P values are from an unpaired t-test; n = 8 independent means comprised each of 3 biological replicates (main panel), n = 3 (inset) biological replicates; light grey dots, not significant (P > 0.05, <1.5-fold change). Data are reproduced in Supplementary Table 6. c, Proteins affected >2-fold in levels in respiration-deficient subunit knockout cell lines. Colour key according to b. Bold, proteins listed in MitoCarta2.0. d, Proteins associated with GO terms and groups outlined in Fig. 2d.
Extended Data Figure 6 Mapping of complex I subunit levels onto the structure.
a, Subunit levels in complex I accessory subunit knockout lines were mapped to homologous subunits in the bovine single-particle electron cryo-microscopy structure of complex I (ref. 9) as in Fig. 3b. Both sides of complex I are shown. Median ratio data used in the preparation of this figure can be found in Supplementary Table 7. b, Opposite side view of Fig. 3c. n.d., dark grey shading on the structures, subunits not quantified. Subunits not clustered to modules removed for clarity.
Extended Data Figure 7 mRNA expression levels in selected accessory subunit knockout lines.
Transcripts were measured for nuclear-encoded complex I subunit genes along with control genes from complex II (SDHA), complex III (UQCRC1, UQCRFS1), complex IV (COX4L1, NDUFA4), complex V (ATP5B, ATP5H) and mt-ribosome (MRPS2, MRPL46) in knockout lines (performed in duplicate).
Extended Data Figure 8 Analysis of assembly factor knockout lines.
a, Mitochondrial proteins from the indicated cell lines were separated by SDS–PAGE and subjected to western blot analysis. b, Volcano plots showing fold changes versus P values for the mitochondrial proteins in assembly factor knockout cell lines. P values are from an unpaired t-test; n = 3 biological replicates; coloured dots are according to the key at bottom right. n.s., not significant (P > 0.05). c, Subunit levels mapped to homologous subunits in the bovine single-particle electron cryo-microscopy structure as in Fig. 3b. n.d., dark grey shading on the structures, subunits not quantified. Both sides of complex I are shown.
Extended Data Figure 9 Characterization of DMAC1 and ATP5SL.
a, ATP5SL-knockout mitochondria were solubilized in Triton X-100 or digitonin and analysed by BN–PAGE and immunoblotting with the indicated antibodies. b, As in a using DMAC1-knockout mitochondria. c, Volcano plots showing fold changes versus P values for the mitochondrial proteins in ATP5SL and DMAC1 knockout cell lines. P values are from an unpaired t-test; n = 3 biological replicates; coloured dots represent complex I subunits depicted in the key; n.s., P > 0.05. d, Subunit levels mapped to homologous subunits in the bovine single-particle electron cryo-microscopy structure as for Fig. 3b. n.d., dark grey shading on the structures, not quantified. Both sides of complex I are shown. e, Mitochondria isolated from DMAC1 cells complemented with DMAC1Flag were resuspended in isotonic buffer, hypoosmotic swelling buffer, or Triton X-100 followed by proteinase K (PK) incubation where indicated. Alternately, mitochondria were treated with 100 mM Na2CO3 and membrane-integral (pellet) and soluble or peripherally attached (supernatant, SN) proteins were separated by ultracentrifugation. Samples were analysed by SDS–PAGE and immunoblotting for TOMM20 (outer mitochondrial membrane protein); MIC10 (integral inner membrane protein exposed to intermembrane space); NDUFAF1 (matrix, soluble); and NDUFS2 (matrix, peripheral). f, DMAC1-knockout cells complemented with DMAC1Flag were analysed by immunofluorescence microscopy with the indicated antibodies. Scale bar, 20 μm. Representative result from 3 independent experiments. g, Cells were pulsed with [35S]methionine for 1 h and chased for the indicated times. Isolated mitochondria were solubilized in Triton X-100 and analysed by 2D-PAGE and autoradiography. ◊, 600 kDa complex; #, subcomplex containing ND1 and ND2.
Supplementary information
Supplementary Information
This file contains Supplementary Figure 1, uncropped scans with size marker indications and Supplementary Table 1, detailed information on targeting strategies and resulting indels detected in knockout cell lines generated in this study. (PDF 28333 kb)
Supplementary Data
This file contains Supplementary Tables 2-12, representing the proteomic data generated in this study and a list of primer sequences used for mRNA expression level analysis. (XLSX 18192 kb)
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Stroud, D., Surgenor, E., Formosa, L. et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538, 123–126 (2016). https://doi.org/10.1038/nature19754
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DOI: https://doi.org/10.1038/nature19754
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