scholarly journals Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

2010 ◽  
Vol 30 (12) ◽  
pp. 3038-3047 ◽  
Author(s):  
Ester Perales-Clemente ◽  
Erika Fernández-Vizarra ◽  
Rebeca Acín-Pérez ◽  
Nieves Movilla ◽  
María Pilar Bayona-Bafaluy ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Mouse Cell ◽  
Assembly Process ◽  
Large Size ◽  
Assembly Pathway ◽  
Complex Process ◽  
Entry Points ◽  
Complex I Assembly

ABSTRACT Complex I (CI) is the largest enzyme of the mammalian mitochondrial respiratory chain. The biogenesis of the complex is a very complex process due to its large size and number of subunits (45 subunits). The situation is further complicated due to the fact that its subunits have a double genomic origin, as seven of them are encoded by the mitochondrial DNA. Understanding of the assembly process and characterization of the involved factors has advanced very much in the last years. However, until now, a key part of the process, that is, how and at which step the mitochondrially encoded CI subunits (ND subunits) are incorporated in the CI assembly process, was not known. Analyses of several mouse cell lines mutated for three ND subunits allowed us to determine the importance of each one for complex assembly/stability and that there are five different steps within the assembly pathway in which some mitochondrially encoded CI subunit is incorporated.

scholarly journals Identification and Characterization of a Common Set of Complex I Assembly Intermediates in Mitochondria from Patients with Complex I Deficiency

2003 ◽  
Vol 278 (44) ◽  
pp. 43081-43088 ◽  
Author(s):  
Hana Antonicka ◽  
Isla Ogilvie ◽  
Tanja Taivassalo ◽  
Roberto P. Anitori ◽  
Ronald G. Haller ◽  
...  
Keyword(s):  
Complex I ◽  
Complex I Deficiency ◽  
Complex I Assembly ◽  
Identification And Characterization

scholarly journals LINC00116 codes for a mitochondrial peptide linking respiration and lipid metabolism

2019 ◽  
Vol 116 (11) ◽  
pp. 4940-4945 ◽  
Author(s):  
Anastasia Chugunova ◽  
Elizaveta Loseva ◽  
Pavel Mazin ◽  
Aleksandra Mitina ◽  
Tsimafei Navalayeu ◽  
...  
Keyword(s):  
Complex I ◽  
Noncoding Rna ◽  
Cytochrome B5 ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Mouse Cell ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Small Peptides ◽  
Mitochondrial Respiratory Chain Complex ◽  
Cellular Processes

Genes coding for small peptides have been frequently misannotated as long noncoding RNA (lncRNA) genes. Here we have demonstrated that one such transcript is translated into a 56-amino-acid-long peptide conserved in chordates, corroborating the work published while this manuscript was under review. The Mtln peptide could be detected in mitochondria of mouse cell lines and tissues. In line with its mitochondrial localization, lack of the Mtln decreases the activity of mitochondrial respiratory chain complex I. Unlike the integral components and assembly factors of NADH:ubiquinone oxidoreductase, Mtln does not alter its enzymatic activity directly. Interaction of Mtln with NADH-dependent cytochrome b5 reductase stimulates complex I functioning most likely by providing a favorable lipid composition of the membrane. Study of Mtln illuminates the importance of small peptides, whose genes might frequently be misannotated as lncRNAs, for the control of vitally important cellular processes.

scholarly journals Nuclear Suppression of Mitochondrial Defects in Cells without the ND6 Subunit

2006 ◽  
Vol 26 (3) ◽  
pp. 1077-1086 ◽  
Author(s):  
Jian-Hong Deng ◽  
Youfen Li ◽  
Jeong Soon Park ◽  
Jun Wu ◽  
Peiqing Hu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Complex I ◽  
Mouse Cell ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation ◽  
Nuclear Background ◽  
Mitochondrial Defects ◽  
Nd5 Gene ◽  
Respiratory Complex I ◽  
Complex I Assembly

ABSTRACT Previously, we characterized a mouse cell line, 4A, carrying a mitochondrial DNA mutation in the subunit for respiratory complex I, NADH dehydrogenase, in the ND6 gene. This mutation abolished the complex I assembly and disrupted the respiratory function of complex I. We now report here that a galactose-resistant clone, 4AR, was isolated from the cells carrying the ND6 mutation. 4AR still contained the homoplasmic mutation, and apparently there was no ND6 protein synthesis, whereas the assembly of other complex I subunits into complex I was recovered. Furthermore, the respiratory activity and mitochondrial membrane potential were fully recovered. To investigate the genetic origin of this compensation, the mitochondrial DNA (mtDNA) from 4AR was transferred to a new nuclear background. The transmitochondrial lines failed to grow in galactose medium. We further transferred mtDNA with a nonsense mutation at the ND5 gene to the 4AR nuclear background, and a suppression for mitochondrial deficiency was observed. Our results suggest that change(s) in the expression of a certain nucleus-encoded factor(s) can compensate for the absence of the ND6 or ND5 subunit.

scholarly journals Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

2016 ◽  
Vol 113 (46) ◽  
pp. 13063-13068 ◽  
Author(s):  
Irene Lopez-Fabuel ◽  
Juliette Le Douce ◽  
Angela Logan ◽  
Andrew M. James ◽  
Gilles Bonvento ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Complex I ◽  
Structural Organization ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Mitochondrial Ros ◽  
Complex I Assembly

Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.

scholarly journals Development and Characterization of a Conditional Mitochondrial Complex I Assembly System

2004 ◽  
Vol 279 (13) ◽  
pp. 12406-12413 ◽  
Author(s):  
Nagendra Yadava ◽  
Toby Houchens ◽  
Prasanth Potluri ◽  
Immo E. Scheffler
Keyword(s):  
Complex I ◽  
Assembly System ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Complex I Assembly

scholarly journals GRIM-19 Is Essential for Maintenance of Mitochondrial Membrane Potential

2008 ◽  
Vol 19 (5) ◽  
pp. 1893-1902 ◽  
Author(s):  
Hao Lu ◽  
Xinmin Cao
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Mitochondrial Membrane ◽  
Transmembrane Potential ◽  
Mitochondrial Respiratory Chain ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mitochondrial Localization ◽  
N Terminus ◽  
Complex I Assembly

GRIM-19 was found to copurify with complex I of mitochondrial respiratory chain and subsequently was demonstrated to be involved in complex I assembly and activity. To further understand its function in complex I, we dissected its functional domains by generating a number of deletion, truncation, and point mutants. The mitochondrial localization sequences were located at the N-terminus. Strikingly, deletion of residues 70–80, 90–100, or the whole C-terminal region (70–144) led to a loss of mitochondrial transmembrane potential (ΔΨm). However, similar deletions of another two complex I subunits, NDUFA9 and NDUFS3, did not show such effect. We also found that deletion of the last 10 residues affected GRIM-19's ability to be assembled to complex I. We constructed a dominant-negative mutant containing the N-terminal 60 and the last C-terminal 10 residues, which could be assembled into complex I, but failed to maintain normal ΔΨm. Cells overexpressing this mutant did not spontaneously undergo cell death, but were sensitized to apoptosis induced by cell death agents. Our results demonstrate that GRIM-19 is required for electron transfer activity of complex I, and disruption of ΔΨm by GRIM-19 mutants enhances the cells' sensitivity to apoptotic stimuli.

scholarly journals An antibody toolbox to track complex I assembly defines AIF’s mitochondrial function

2020 ◽  
Vol 219 (10) ◽  
Author(s):  
Anjaneyulu Murari ◽  
Shauna-Kay Rhooms ◽  
Naga Sri Goparaju ◽  
Maximino Villanueva ◽  
Edward Owusu-Ansah
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Biosynthetic Pathway ◽  
Mitochondrial Proteins ◽  
Contact Site ◽  
Apoptosis Inducing Factor ◽  
Complex I Assembly

An ability to comprehensively track the assembly intermediates (AIs) of complex I (CI) biogenesis in Drosophila will enable the characterization of the precise mechanism(s) by which various CI regulators modulate CI assembly. Accordingly, we generated 21 novel antibodies to various mitochondrial proteins and used this resource to characterize the mechanism by which apoptosis-inducing factor (AIF) regulates CI biogenesis by tracking the AI profile observed when AIF expression is impaired. We find that when the AIF–Mia40 translocation complex is disrupted, the part of CI that transfers electrons to ubiquinone is synthesized but fails to progress in the CI biosynthetic pathway. This is associated with a reduction in intramitochondrial accumulation of the Mia40 substrate, MIC19. Importantly, knockdown of either MIC19 or MIC60, components of the mitochondrial contact site and cristae organizing system (MICOS), fully recapitulates the AI profile observed when AIF is inhibited. Thus, AIF’s effect on CI assembly is principally due to compromised intramitochondrial transport of the MICOS 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.

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