scholarly journals Demonstration of a New Pathogenic Mutation in Human Complex I Deficiency: A 5-bp Duplication in the Nuclear Gene Encoding the 18-kD (AQDQ) Subunit

1998 ◽  
Vol 62 (2) ◽  
pp. 262-268 ◽  
Author(s):  
Lambert van den Heuvel ◽  
Wim Ruitenbeek ◽  
Roel Smeets ◽  
Zully Gelman-Kohan ◽  
Orly Elpeleg ◽  
...  
Keyword(s):  
Complex I ◽  
Nuclear Gene ◽  
Pathogenic Mutation ◽  
Gene Encoding ◽  
Complex I Deficiency ◽  
Human Complex

scholarly journals Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases

2012 ◽  
Vol 35 (5) ◽  
pp. 737-747 ◽  
Author(s):  
S. Koene ◽  
R. J. Rodenburg ◽  
M. S. van der Knaap ◽  
M. A. A. P. Willemsen ◽  
W. Sperl ◽  
...  
Keyword(s):  
Complex I ◽  
Nuclear Gene ◽  
Disease Course ◽  
Complex I Deficiency ◽  
Gene Defects

Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency

2005 ◽  
Vol 289 (4) ◽  
pp. C881-C890 ◽  
Author(s):  
Werner J. H. Koopman ◽  
Henk-Jan Visch ◽  
Sjoerd Verkaart ◽  
Lambertus W. P. J. van den Heuvel ◽  
Jan A. M. Smeitink ◽  
...  
Keyword(s):  
Form Factor ◽  
Aspect Ratio ◽  
Complex I ◽  
Mitochondrial Morphology ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Mitochondrial Network ◽  
Mitochondrial Structure ◽  
Complex I Deficiency ◽  
Complex I Activity ◽  
Human Complex

Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the oxidative phosphorylation system, and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in adult life. The changes in mitochondrial structure and function that are at the basis of the clinical symptoms are poorly understood. Video-rate confocal microscopy of cells pulse-loaded with mitochondria-specific rhodamine 123 followed by automated analysis of form factor (combined measure of length and degree of branching), aspect ratio (measure of length), and number of revealed marked differences between primary cultures of skin fibroblasts from 13 patients with an isolated complex I deficiency. These differences were independent of the affected subunit, but plotting of the activity of complex I, normalized to that of complex IV, against the ratio of either form factor or aspect ratio to number revealed a linear relationship. Relatively small reductions in activity appeared to be associated with an increase in form factor and never with a decrease in number, whereas relatively large reductions occurred in association with a decrease in form factor and/or an increase in number. These results demonstrate that complex I activity and mitochondrial structure are tightly coupled in human isolated complex I deficiency. To further prove the relationship between aberrations in mitochondrial morphology and pathological condition, fibroblasts from two patients with a different mutation but a highly fragmented mitochondrial phenotype were fused. Full restoration of the mitochondrial network demonstrated that this change in mitochondrial morphology was indeed associated with human complex I deficiency.

Ca2+-mobilizing agonists increase mitochondrial ATP production to accelerate cytosolic Ca2+removal: aberrations in human complex I deficiency

2006 ◽  
Vol 291 (2) ◽  
pp. C308-C316 ◽  
Author(s):  
Henk-Jan Visch ◽  
Werner J. H. Koopman ◽  
Dimphy Zeegers ◽  
Sjenet E. van Emst-de Vries ◽  
Frank J. M. van Kuppeveld ◽  
...  
Keyword(s):  
Digital Imaging ◽  
Complex I ◽  
Removal Rate ◽  
Mitochondrial Matrix ◽  
Atp Production ◽  
Complex I Deficiency ◽  
Deficient Patient ◽  
Atp Supply ◽  
Human Complex

Previously, we reported that both the bradykinin (Bk)-induced increase in mitochondrial ATP concentration ([ATP]M) and the rate of cytosolic Ca2+removal are significantly decreased in skin fibroblasts from a patient with an isolated complex I deficiency. Here we demonstrate that the mitochondrial Ca2+indicator rhod-2 can be used to selectively buffer the Bk-induced increase in mitochondrial Ca2+concentration ([Ca2+]M) and, consequently, the Ca2+-stimulated increase in [ATP]M, thus allowing studies of how the increase in [ATP]Mand the cytosolic Ca2+removal rate are related. Luminometry of healthy fibroblasts expressing either aequorin or luciferase in the mitochondrial matrix showed that rhod-2 dose dependently decreased the Bk-induced increase in [Ca2+]Mand [ATP]Mby maximally 80 and 90%, respectively. Digital imaging microscopy of cells coloaded with the cytosolic Ca2+indicator fura-2 revealed that, in parallel, rhod-2 maximally decreased the cytosolic Ca2+removal rate by 20%. These findings demonstrate that increased mitochondrial ATP production is required for accelerating cytosolic Ca2+removal during stimulation with a Ca2+-mobilizing agonist. In contrast, complex I-deficient patient fibroblasts displayed a cytosolic Ca2+removal rate that was already decreased by 40% compared with healthy fibroblasts. Rhod-2 did not further decrease this rate, indicating the absence of mitochondrial ATP supply to the cytosolic Ca2+pumps. This work reveals the usefulness of rhodamine-based Ca2+indicators in examining the role of intramitochondrial Ca2+in mitochondrial (patho) physiology.

scholarly journals High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency

2010 ◽  
Vol 42 (10) ◽  
pp. 851-858 ◽  
Author(s):  
Sarah E Calvo ◽  
Elena J Tucker ◽  
Alison G Compton ◽  
Denise M Kirby ◽  
Gabriel Crawford ◽  
...  
Keyword(s):  
High Throughput ◽  
Complex I ◽  
Complex I Deficiency ◽  
Pooled Sequencing ◽  
Human Complex

The molecular basis of human complex I deficiency

IUBMB Life ◽  
2011 ◽  
pp. n/a-n/a ◽  
Author(s):  
Elena J. Tucker ◽  
Alison G. Compton ◽  
Sarah E. Calvo ◽  
David R. Thorburn
Keyword(s):  
Molecular Basis ◽  
Complex I ◽  
Complex I Deficiency ◽  
Human Complex

scholarly journals Analysis of the Assembly Profiles for Mitochondrial- and Nuclear-DNA-Encoded Subunits into Complex I

2007 ◽  
Vol 27 (12) ◽  
pp. 4228-4237 ◽  
Author(s):  
Michael Lazarou ◽  
Matthew McKenzie ◽  
Akira Ohtake ◽  
David R. Thorburn ◽  
Michael T. Ryan
Keyword(s):  
Complex I ◽  
Nuclear Dna ◽  
De Novo ◽  
Nuclear Gene ◽  
Subunit Exchange ◽  
Mitochondrial Inner Membrane ◽  
Large Size ◽  
Membrane Defects ◽  
Complex I Assembly ◽  
Human Complex

ABSTRACT Complex I of the respiratory chain is composed of at least 45 subunits that assemble together at the mitochondrial inner membrane. Defects in human complex I result in energy generation disorders and are also implicated in Parkinson's disease and altered apoptotic signaling. The assembly of this complex is poorly understood and is complicated by its large size and its regulation by two genomes, with seven subunits encoded by mitochondrial DNA (mtDNA) and the remainder encoded by nuclear genes. Here we analyzed the assembly of a number of mtDNA- and nuclear-gene-encoded subunits into complex I. We found that mtDNA-encoded subunits first assemble into intermediate complexes and require significant chase times for their integration into the holoenzyme. In contrast, a set of newly imported nuclear-gene-encoded subunits integrate with preexisting complex I subunits to form intermediates and/or the fully assembly holoenzyme. One of the intermediate complexes represents a subassembly associated with the chaperone B17.2L. By using isolated patient mitochondria, we show that this subassembly is a productive intermediate in complex I assembly since import of the missing subunit restores complex I assembly. Our studies point to a mechanism of complex I biogenesis involving two complementary processes, (i) synthesis of mtDNA-encoded subunits to seed de novo assembly and (ii) exchange of preexisting subunits with newly imported ones to maintain complex I homeostasis. Subunit exchange may also act as an efficient mechanism to prevent the accumulation of oxidatively damaged subunits that would otherwise be detrimental to mitochondrial oxidative phosphorylation and have the potential to cause disease.

Disruption of a Nuclear Gene Encoding a Mitochondrial Gamma Carbonic Anhydrase Reduces Complex I and Supercomplex I+III2 Levels and Alters Mitochondrial Physiology in Arabidopsis

2005 ◽  
Vol 350 (2) ◽  
pp. 263-277 ◽  
Author(s):  
Mariano Perales ◽  
Holger Eubel ◽  
Jesco Heinemeyer ◽  
Alejandro Colaneri ◽  
Eduardo Zabaleta ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Complex I ◽  
Nuclear Gene ◽  
Gene Encoding ◽  
Gamma Carbonic Anhydrase
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