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Human mitochondrial complex I assembly: A dynamic and versatile process

Nijmegen Centre for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 11/2007; 1767(10):1215-27. DOI: 10.1016/j.bbabio.2007.07.008
Source: PubMed

ABSTRACT One can but admire the intricate way in which biomolecular structures are formed and cooperate to allow proper cellular function. A prominent example of such intricacy is the assembly of the five inner membrane embedded enzymatic complexes of the mitochondrial oxidative phosphorylation (OXPHOS) system, which involves the stepwise combination of >80 subunits and prosthetic groups encoded by both the mitochondrial and nuclear genomes. This review will focus on the assembly of the most complicated OXPHOS structure: complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3). Recent studies into complex I assembly in human cells have resulted in several models elucidating a thus far enigmatic process. In this review, special attention will be given to the overlap between the various assembly models proposed in different organisms. Complex I being a complicated structure, its assembly must be prone to some form of coordination. This is where chaperone proteins come into play, some of which may relate complex I assembly to processes such as apoptosis and even immunity.

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Available from: Leo G J Nijtmans, Dec 18, 2013
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    • "The exact mechanisms of energy transduction between the redox reaction at the terminal cluster N2 and proton translocation in the membrane part are still not known. Recent studies [3] [4] have significantly improved our understanding of the structure, the proton translocation machinery [4] [5] and assembly of complex I [6] but many aspects of the enzyme's regulation require elucidation. An intriguing feature of mitochondrial complex I from several vertebrate species and yeast is the existence of two functionally and structurally different states of the enzyme: active, A-form and de-active or Biochimica et Biophysica Acta 1837 (2014) 929–939 Abbreviations: A/D, active/de-active transition; AH, amphipathic helix; BN-PAGE, blue native polyacrylamide gel electrophoresis; DIGE, difference gel electrophoresis; dSDS-PAGE, double SDS-PAGE; DTT, dithiothreitol; F-NHS, fluorescein-N-hydroxysulfosuccinimide ester; hrCN-PAGE, high resolution clear native polyacrylamide gel electrophoresis; LHON, Leber's hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; NADH, dihydronicotinamide adenine dinucleotide; NAI, N-acetylimidazole; NEM, N-ethylmaleimide; NHS, N-hydroxysuccinimide; nLC- ESI-MSMS, nano-HPLC electrospray ionisation tandem mass spectrometry; Q 1 , ubi- quinone-1,2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone; ROS, reactive oxygen species; SMP, submitochondrial particles; TMS, transmembrane segment; TNM, tetranitromethane ⁎ Corresponding author. "
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    ABSTRACT: An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) to the de-active, (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I + III2 + IV (S1) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39 kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.
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    • "In human, the NADH dehydrogenase module (comprising notably NDUFV2/24 kD, NDUFV1/51 kD and NDUFS1/75 kD) is distinct from the hydrogenase module (comprising notably NDUFS3/Nd9, NDUFS2/ Nd7, NDUFS7/PSTT, NDUFS8/TYKY) and these two fractions (fractions FP and IP, respectively, e.g. Sazanov et al., 2000) are assembled separately (Antonicka et al., 2003; Vogel et al., 2007). In NUO7 and NUO9 knockdown Chlamydomonas mutants, while we found the soluble ~200 kD NADH dehydrogenase activity along with the 75 kD (NDUFS1) subunit detected in membrane extract (data not shown), subunits NDUFS7/ PSTT and NDUFS8/TYKY of the hydrogenase module are absent. "
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    ABSTRACT: In Chlamydomonas, unlike in flowering plants, genes coding for Nd7 (NAD7/49kDa) and Nd9 (NAD9/30kDa) core subunits of mitochondrial respiratory-chain complex I are nucleus-encoded. Both genes possess all the features that facilitate their expression and proper import of the polypeptides in mitochondria. By inactivating their expression by RNA interference or insertional mutagenesis, we show that both subunits are required for complex I assembly and activity. Inactivation of complex I impairs the cell growth rate, reduces the respiratory rate, leads to lower intracellular ROS production and lower expression of ROS scavenging enzymes, and is associated to a diminished capacity to concentrate CO2 without compromising photosynthetic capacity.
    Mitochondrion 12/2013; DOI:10.1016/j.mito.2013.11.004 · 3.52 Impact Factor
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    • "In control cells, NDUFA4 never occurred in positions where CI migrates alone; on the contrary, it always comigrated with CIV subunits, either at positions where CIV migrates alone, or assembled in supercomplex I+III 2 +IV n . Moreover , in CI KO samples, where only four of the CI subunits are detected (NDUFS7, NDUFS3, NDUFA8, and ND1—comigrating in a previously described subcomplex [Vogel et al., 2007]), NDUFA4 was still present and comigrated with CIV. In contrast, in CIV KO cells, NDUFA4 was deleted, together with all CIV proteins (Figure 1A). "
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    ABSTRACT: The oxidative phosphorylation system is one of the best-characterized metabolic pathways. In mammals, the protein components and X-ray structures are defined for all complexes except complex I. Here, we show that NDUFA4, formerly considered a constituent of NADH Dehydrogenase (CI), is instead a component of the cytochrome c oxidase (CIV). Deletion of NDUFA4 does not perturb CI. Rather, proteomic, genetic, evolutionary, and biochemical analyses reveal that NDUFA4 plays a role in CIV function and biogenesis. The change in the attribution of the NDUFA4 protein requires renaming of the gene and reconsideration of the structure of CIV. Furthermore, NDUFA4 should be considered a candidate gene for CIV rather than CI deficiencies in humans.
    Cell metabolism 08/2012; 16(3):378-86. DOI:10.1016/j.cmet.2012.07.015 · 16.75 Impact Factor
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