The iron–sulphur protein Ind1 is required for effective complex I assembly

Bych, Katrine; Kerscher, Stefan; Netz, Daili J. A.; Pierik, Antonio J.; Zwicker, Klaus; Huynen, Martijn A.; Lill, Roland; Brandt, Ulrich; Balk, Janneke

doi:10.1038/emboj.2008.98

Cited by 156 publications

(200 citation statements)

References 39 publications

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“…The assembly and stability of such a large multiprotein complex requires specific chaperone and assembly factors, six of which have been implicated in human CI deficiency, including NDUFAF1-NDUFAF4 Ogilvie et al, 2005;Saada et al, 2009;Vogel et al, 2005), C8ORF38 and C20ORF7 (Gerards et al, 2009;Sugiana et al, 2008). Others such as Ecsit (Vogel et al, 2007), AIF (Vahsen et al, 2004) and IndI (Bych et al, 2008) are required for CI assembly, but have not yet been implicated in human disease.…”

Section: Discussionmentioning

confidence: 99%

MidA is a putative methyltransferase that is required for mitochondrial complex I function

Carilla-Latorre

Gallardo

Annesley

et al. 2010

Journal of Cell Science

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SummaryDictyostelium and human MidA are homologous proteins that belong to a family of proteins of unknown function called DUF185. Using yeast two-hybrid screening and pull-down experiments, we showed that both proteins interact with the mitochondrial complex I subunit NDUFS2. Consistent with this, Dictyostelium cells lacking MidA showed a specific defect in complex I activity, and knockdown of human MidA in HEK293T cells resulted in reduced levels of assembled complex I. These results indicate a role for MidA in complex I assembly or stability. A structural bioinformatics analysis suggested the presence of a methyltransferase domain; this was further supported by site-directed mutagenesis of specific residues from the putative catalytic site. Interestingly, this complex I deficiency in a Dictyostelium midA -mutant causes a complex phenotypic outcome, which includes phototaxis and thermotaxis defects. We found that these aspects of the phenotype are mediated by a chronic activation of AMPK, revealing a possible role of AMPK signaling in complex I cytopathology.

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Section: Discussionmentioning

confidence: 99%

MidA is a putative methyltransferase that is required for mitochondrial complex I function

Carilla-Latorre

Gallardo

Annesley

et al. 2010

Journal of Cell Science

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“…The CFD1, Npb35, and huNbp35 (formally Nubp1) proteins were demonstrated to be involved in cytoplasmic [Fe-S] cluster metabolism (31,32). Ind1 was demonstrated to be involved in the maturation of [Fe-S] clusters in the mitochondrial enzyme NADH:ubiquinone oxidoreductase (33). There is currently no report of any of these proteins hydrolyzing ATP.…”

Section: Nifusvcyse1) Involved In the Biosynthesis Of [Fe-s] Clustersmentioning

confidence: 99%

Bacterial ApbC Protein Has Two Biochemical Activities That Are Required for in Vivo Function

Boyd

Sondelski

Downs

2009

Journal of Biological Chemistry

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Analysis of the metabolic network anchored to thiamine biosynthesis in S. enterica identified lesions in three non-isc or -suf loci that compromise Fe-S metabolism as follows: apbC, apbE, and rseC (17-21). This metabolic system was subsequently used to dissect a role for cyaY and gshA in [Fe-S] cluster metabolism (6,22,23). Of these, the apbC (mrp in E. coli) locus was identified as the predominant site of lesions that altered thiamine synthesis by disrupting [Fe-S] cluster metabolism (17,18).ApbC is a member of the ParA subfamily of proteins that have a wide array of functions, including electron transfer (24), initiation of cell division (25), and DNA segregation (26,27). Importantly, ATP hydrolysis is required for function of all well characterized members of this subfamily, and all members contain a "deviant" Walker A motif, which contains two lysine residues instead of one (GKXXXGK(S/T)) (28). ApbC has been shown to hydrolyze ATP (17).Recently, five proteins with a high degree of identity to ApbC have been shown to be involved in [Fe-S] cluster metabolism in eukaryotes. The sequence alignments of the central portion of these proteins and bacterial ApbC are shown in Fig. 1. HCF101 was demonstrated to be involved in chloroplast [Fe-S] cluster metabolism (29, 30). The CFD1, Npb35, and huNbp35 (formally Nubp1) proteins were demonstrated to be involved in cytoplasmic [Fe-S] cluster metabolism (31,32). Ind1 was demonstrated to be involved in the maturation of [Fe-S] clusters in the mitochondrial enzyme NADH:ubiquinone oxidoreductase (33). There is currently no report of any of these proteins hydrolyzing ATP.Biochemical analysis of ApbC indicated that it could bind and transfer [Fe-S] clusters to Saccharomyces cerevisiae apo-isopropylmalate isomerase (34). Additional genetic studies indicated that ApbC has a degree of functional redundancy with IscU, a known [Fe-S] cluster scaffolding protein (35,36).In this study we investigate the correlation between the biochemical properties of ApbC (i.e. ATPase activity, [Fe-S] cluster binding, and [Fe-S] cluster transfer rates) and the in vivo function of this protein. This is the first detailed kinetic analysis of ATP hydrolysis for a member of the ParA subfamily of deviant Walker A proteins and the first functional analysis of a member of the ever expanding family of ApbC/Nbp35 proteins. Data presented indicate that noncomplementing variants have distinct biochemical properties that place them in three distinct classes.

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“…Moreover, several of these assembly factors have been associated with roles other than Complex I biogenesis, indicating a possible link between Complex I activity and other cellular processes (20). Other proteins described as Complex I assembly factors are proteins involved in the assembly of the iron-sulfur proteins such as Ind1 (21,22), suggesting that the assembly of Complex I without Fe-S centers is not possible.…”

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Insights into the Composition and Assembly of the Membrane Arm of Plant Complex I through Analysis of Subcomplexes in Arabidopsis Mutant Lines

Meyer

Solheim

Tanz

et al. 2011

Journal of Biological Chemistry

127

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NADH-ubiquinone oxidoreductase (Complex I, EC 1.6.5.3) is the largest complex of the mitochondrial respiratory chain. In eukaryotes, it is composed of more than 40 subunits that are encoded by both the nuclear and mitochondrial genomes. Plant Complex I differs from the enzyme described in other eukaryotes, most notably due to the large number of plant-specific subunits in the membrane arm of the complex. The elucidation of the assembly pathway of Complex I has been a longstanding research aim in cellular biochemistry. We report the study of Arabidopsis mutants in Complex I subunits using a combination of Blue-Native PAGE and immunodetection to identify stable subcomplexes containing Complex I components, along with mass spectrometry analysis of Complex I components in membrane fractions and two-dimensional diagonal Tricine SDS-PAGE to study the composition of the largest subcomplex. Four subcomplexes of the membrane arm of Complex I with apparent molecular masses of 200, 400, 450, and 650 kDa were observed. We propose a working model for the assembly of the membrane arm of Complex I in plants and assign putative roles during the assembly process for two of the subunits studied.NADH-ubiquinone oxidoreductase (Complex I, EC 1.6.5.3) 2 is the main entry point for electrons in the mitochondrial respiratory chain. It is the largest and most complicated complex of the respiratory chain. In higher eukaryotes, it is composed of more than 40 subunits. It has a dual genetic origin: 5 to 9 subunits are encoded by the mitochondrial genome, and the others are encoded by the nuclear genome. This complex consists of two parts forming an L-shaped structure: the membrane arm forms the base of the L and is embedded within the inner mitochondrial membrane, while the matrix arm forms the side of the L, bonded at one end of the membrane arm and perpendicularly protruding into the soluble matrix space. The matrix arm contains all the Fe-S clusters and the NADH oxidizing activity, while the membrane arm contains the ubiquinone-binding site. The detailed composition, mechanistic analysis of function, and elucidation of the assembly pathway of Complex I have been long-standing areas of research in a range of different species.The localization of the different subunits within the two arms of mitochondrial Complex I has been intensively investigated in the bovine enzyme. This purified Complex I has been fragmented into three parts: , corresponding to the matrix arm, ␤, corresponding to the membrane arm, and ␣, the matrix arm and some membrane subunits that allow the anchoring of the matrix arm in the inner membrane (1). Complex I assembly has been most intensively investigated using mutants of genes encoding Complex I subunits in Neurospora crassa (2) and human (3, 4). Some mutants lacking one Complex I subunits do not contain a fully assembled Complex I but accumulate stable subcomplexes of Complex I. The formation of stable assembly subcomplexes can be identified using antibodies raised against specific Complex I subunits (2-4). Other a...

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The iron–sulphur protein Ind1 is required for effective complex I assembly

Cited by 156 publications

References 39 publications

MidA is a putative methyltransferase that is required for mitochondrial complex I function

MidA is a putative methyltransferase that is required for mitochondrial complex I function

Bacterial ApbC Protein Has Two Biochemical Activities That Are Required for in Vivo Function

Insights into the Composition and Assembly of the Membrane Arm of Plant Complex I through Analysis of Subcomplexes in Arabidopsis Mutant Lines

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