Structure of mammalian respiratory complex I

Zhu, Jiapeng; Vinothkumar, Kutti R.; Hirst, Judy

doi:10.1038/nature19095

Cited by 509 publications

(754 citation statements)

References 45 publications

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“…42,47 For mitoribosome subunit mapping, the human mitoribosome structure (PDB: 3J9M) was used. 48 For complexes III and IV, homologous human subunits were mapped to the bovine structures PDB: 1BGY and 5B1A, respectively, 49,50 whereas for complex II homologous human subunits were mapped to those found in the porcine structure (PDB: 1ZOY).…”

Section: Mitochondrial Protein Synthesis Assaymentioning

confidence: 99%

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

101

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Section: Mitochondrial Protein Synthesis Assaymentioning

confidence: 99%

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

101

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“…The NDUFB8 subunit is essential for the assembly, structure stability and function of the complex [39,46] and its knockdown decreases complex I activity in animals [10]. We, therefore, reasoned that NDUFB8 deficiency should reflect the entire complex.…”

Section: Discussionmentioning

confidence: 99%

“…Serial 3 μm thick sections were stained with primary antibodies (all from Abcam) against complex I (NDUFB8, ab110242, dilution 1:300), complex II (anti-SDHA, ab14715, dilution 1:4000), complex III (anti-UQCRC2, ab14745, dilution 1:10,000), complex IV (COX-I, ab14705, dilution 1:10,000), complex V (ATP-synthase, ab14748, dilution 1:10,000), and the mitochondrial membrane marker porin (VDAC1, ab14734, dilution 1:10,000). We chose the NDUFB8 subunit because it is central to complex I assembly and function [10,39,46] and has been widely used as a marker of the integrity of the complex [16,40,41]. Sections were deparaffinised in Histoclear and rehydrated in graded ethanol.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

et al. 2017

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Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

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“…ates (41)(42)(43). Although S. cerevisiae has no complex I, that of the yeast Yarrowia lipolytica contains the LYRM6 protein, which is essential for the catalytic activity of this respiratory complex.…”

Section: De Novo Synthesis Of a [2fe-2s] Cluster On The Mitochondrialmentioning

confidence: 99%

“…The Isd11-Acp1 structure may be similar to that of an LYR protein-Acp1 dimer in respiratory complex I (upper inset). The subunit B14 from Bos taurus containing an LYR motif (red) interacts with SDAP-␣ (Acp1), which covalently binds a 4Ј-phosphopantetheine moiety via a conserved serine (orange) (PDB code 5LDW) (41,43).…”

Section: De Novo Synthesis Of a [2fe-2s] Cluster On The Mitochondrialmentioning

confidence: 99%

Iron–sulfur cluster biogenesis and trafficking in mitochondria

Braymer

Lill

2017

Journal of Biological Chemistry

319

293

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The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a multistage, multicompartment process that is essential for a broad range of cellular functions, including genome maintenance, protein translation, energy conversion, and the antiviral response. Genetic and cell biological studies over almost 2 decades have revealed some 30 proteins involved in the synthesis of cellular [2Fe-2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins. Mechanistic aspects of Fe/S protein biogenesis continue to be elucidated by biochemical and ultrastructural investigations. Here, we review recent developments in the pursuit of constructing a comprehensive model of Fe/S protein assembly in the mitochondrion. Ubiquitous iron-sulfur clusters and their synthesis: an overviewIron-sulfur (Fe/S) 2 clusters are inorganic cofactors that are essential for the proper functioning of virtually all biological cells (1). The chemical versatility of these clusters is utilized in fundamental life processes such as energy production, metabolic conversions, DNA maintenance, gene expression regulation, protein translation, and the antiviral response ( Fig. 1) (2-4). In eukaryotes, Fe/S proteins are found in or associated with the mitochondrion, endoplasmic reticulum, cytosol, and the nucleus. These cofactors participate in electron transfer reactions, Lewis acid catalysis, transfer of sulfur atoms, or facilitating structural roles (5, 6). Although the activities of some Fe/S proteins are dispensable for cell survival under certain conditions, for example fungal Fe/S enzymes in the metabolism of amino acids, others such as Fe/S proteins involved in DNA maintenance or protein translation are essential for cell viability (Fig. 1). The growing number of diseases that implicate Fe/S proteins or their assembly factors illustrates the essentiality of the various functions of these protein cofactors (7-9). The phenotypes associated with these "Fe/S diseases" and the in vivo work in model systems such as Saccharomyces cerevisiae and human cell culture have led to a mechanistic model of eukaryotic Fe/S protein biogenesis, in which the sequence of events required for proper synthesis and trafficking of Fe/S clusters has been elucidated (2). This model has been invaluable to diagnosing new mitochondrial disorders, and its continued advancement will enhance the ability for early diagnosis (10 -13). The focus of this review will be on the latest developments of the functional and mechanistic aspects that have advanced the model of mitochondrial Fe/S protein biogenesis.Cells typically maintain a strict balance of iron and sulfide ion concentrations due to their damaging redox reactions when present in excess (14, 15). The cell also uses a complex biosynthetic system to ensure that the sometimes redox-sensitive and labile Fe/S clusters are assembled correctly, trafficked to specific target apoproteins, and remain protected during these processes. This cellular control is exemplified by the 18 known "Fe/S cluster assembly" (ISC) proteins...

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Structure of mammalian respiratory complex I

Cited by 509 publications

References 45 publications

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Iron–sulfur cluster biogenesis and trafficking in mitochondria

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