A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure

10.1038/ng706 ◽  
2001 ◽  
Vol 29 (1) ◽  
pp. 57-60 ◽  
Author(s):  
Pascale de Lonlay ◽  
Isabelle Valnot ◽  
Antoni Barrientos ◽  
Marina Gorbatyuk ◽  
Alexander Tzagoloff ◽  
...  
Keyword(s):  
Liver Failure ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Mitochondrial Respiratory

scholarly journals Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation

2016 ◽  
Vol 27 (14) ◽  
pp. 2161-2171 ◽  
Author(s):  
Charli D. Baker ◽  
Writoban Basu Ball ◽  
Erin N. Pryce ◽  
Vishal M. Gohil
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Phospholipid Composition ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Specific Requirement ◽  
Transport Pathway ◽  
Contact Sites ◽  
Yeast Mutants ◽  
Mitochondrial Respiratory

Mitochondrial membrane phospholipid composition affects mitochondrial function by influencing the assembly of the mitochondrial respiratory chain (MRC) complexes into supercomplexes. For example, the loss of cardiolipin (CL), a signature non–bilayer-forming phospholipid of mitochondria, results in disruption of MRC supercomplexes. However, the functions of the most abundant mitochondrial phospholipids, bilayer-forming phosphatidylcholine (PC) and non–bilayer-forming phosphatidylethanolamine (PE), are not clearly defined. Using yeast mutants of PE and PC biosynthetic pathways, we show a specific requirement for mitochondrial PE in MRC complex III and IV activities but not for their formation, whereas loss of PC does not affect MRC function or formation. Unlike CL, mitochondrial PE or PC is not required for MRC supercomplex formation, emphasizing the specific requirement of CL in supercomplex assembly. Of interest, PE biosynthesized in the endoplasmic reticulum (ER) can functionally substitute for the lack of mitochondrial PE biosynthesis, suggesting the existence of PE transport pathway from ER to mitochondria. To understand the mechanism of PE transport, we disrupted ER–mitochondrial contact sites formed by the ERMES complex and found that, although not essential for PE transport, ERMES facilitates the efficient rescue of mitochondrial PE deficiency. Our work highlights specific roles of non–bilayer-forming phospholipids in MRC function and formation.

Succinimidyl oleate, established inhibitor of CD36/FAT translocase inhibits complex III of mitochondrial respiratory chain

2010 ◽  
Vol 391 (3) ◽  
pp. 1348-1351 ◽  
Author(s):  
Zdeněk Drahota ◽  
Marek Vrbacký ◽  
Hana Nůsková ◽  
Ludmila Kazdová ◽  
Václav Zídek ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Mitochondrial Respiratory

Novel Mycotoxin fromAcremonium exuviarumIs a Powerful Inhibitor of the Mitochondrial Respiratory Chain Complex III

2009 ◽  
Vol 22 (3) ◽  
pp. 565-573 ◽  
Author(s):  
Alexey G. Kruglov ◽  
Maria A. Andersson ◽  
Raimo Mikkola ◽  
Merja Roivainen ◽  
Laszlo Kredics ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Respiratory Chain Complex ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mitochondrial Respiratory

scholarly journals Trib1 deficiency causes brown adipose respiratory chain depletion and mitochondrial disorder

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Xuelian Zhang ◽  
Bin Zhang ◽  
Chenyang Zhang ◽  
Guibo Sun ◽  
Xiaobo Sun
Keyword(s):  
Adipose Tissue ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Knockout Mice ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Adrenoceptor Agonist ◽  
Brown Adipose ◽  
Mitochondrial Respiratory

AbstractTribbles homolog 1 (TRIB1) belongs to the Tribbles family of pseudokinases, which plays a key role in tumorigenesis and inflammation. Although genome-wide analysis shows that TRIB1 expression is highly correlated with blood lipid levels, the relationship between TRIB1 and adipose tissue metabolism remains unclear. Accordingly, the aim of the present study was to explore the role of TRIB1 on mitochondrial function in the brown adipose tissue (BAT). Trib1-knockout mice were established using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. The metabolic function of the BAT was induced by a β3-adrenoceptor agonist and the energy metabolism function of mitochondria in the BAT of mice was evaluated. Trib1-knockout mice exhibited obesity and impaired BAT thermogenesis. In particular, Trib1 knockout reduced the ability of the BAT to maintain body temperature, inhibited β3-adrenoceptor agonist-induced thermogenesis, and accelerated lipid accumulation in the liver and adipose tissues. In addition, Trib1 knockout reduced mitochondrial respiratory chain complex III activity, produced an imbalance between mitochondrial fusion and fission, caused mitochondrial structural damage and dysfunction, and affected heat production and lipid metabolism in the BAT. Conversely, overexpression of Trib1 in 3T3-L1 adipocytes increased the number of mitochondria and improved respiratory function. These findings support the role of Trib1 in regulating the mitochondrial respiratory chain and mitochondrial dynamics by affecting mitochondrial function and thermogenesis in the BAT.

scholarly journals Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage

1992 ◽  
Vol 281 (3) ◽  
pp. 709-715 ◽  
Author(s):  
K Veitch ◽  
A Hombroeckx ◽  
D Caucheteux ◽  
H Pouleur ◽  
L Hue
Keyword(s):  
Respiratory Chain ◽  
Complex I ◽  
Nadh Oxidase ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Biphasic Response ◽  
Ischaemic Damage ◽  
Global Ischaemia ◽  
Complex I Activity ◽  
Mitochondrial Respiratory

Studies of Langendorff-perfused rat hearts have revealed a biphasic response of the mitochondrial respiratory chain to global ischaemia. The initial effect is a 30-40% increase in the rate of glutamate/malate oxidation after 10 min of ischaemia, owing to an increase in the capacity for NADH oxidation. This effect is followed by a progressive decrease in these oxidative activities as the ischaemia is prolonged, apparently owing to damage to Complex I at a site subsequent to the NADH dehydrogenase component. This damage is exacerbated by reperfusion, which causes a further decrease in Complex I activity and also decreases the activities of the other complexes, most notably of Complex III. Perfusion for up to 1 h with anoxic buffer produced only the increase in NADH oxidase activity, and neither anoxia alone, nor anoxia and reperfusion, caused loss of Complex I activity. Perfusing for 3-10 min with anoxic buffer before 1 h of global ischaemia had a significant protective effect against the ischaemia-induced damage to Complex I.

Abstract P277: Cardioprotection Enabled by Proteomic Remodeling of the Mitochondrial Respiratory Chain

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Christopher Lotz ◽  
Ning Deng ◽  
Jun Zhang ◽  
Yueju Wang ◽  
Chenggong Zong ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Respiratory Chain ◽  
Superoxide Production ◽  
Complex Iii ◽  
Molar Ratio ◽  
Label Free ◽  
Enzymatic Function ◽  
Proteomic Approach ◽  
Mitochondrial Respiratory

The mitochondrial respiratory chain is a collection of five multi-protein complexes, whose unobstructed functionality represents a pivotal element at the crossroads of cell death or survival. However, its molecular composition and stochiometric information remains elusive and the adaptive abilities of the chain remain largely unknown. We employed a quantitative proteomic approach to investigate the hypothesis that cardioprotection against ischemic injury is afforded by a salutary proteomic remodeling of the mitochondrial respiratory chain. The respiratory chain of cardiac mitochondria isolated from wild type (WT) mice and from mice expressing a constitutively active protein kinase Cε (AE-PKCε) were characterized using 15N-stable isotope labeled murine models (SILAM), as well as a label-free method in conjunction with high resolution LC-MS/MS, respectively. Enzymatic function of electron transport chain and the ATP synthase were evaluated (n=7/group); and mitochondrial superoxide production was examined by ESR-spectroscopy (n=3/group). Three novel and important observations are made: (i) five individual respiratory complexes exhibited a molar ratio of 1:1:1.4:1.2:4.5 in the WT-heart; (ii) subunits within the five complexes encoded by the mitochondrial genome were expressed at much lower abundance (p<0.05) than those encoded by the nuclear genome; and (iii) Genetic cardioprotection by AE-PKCε elicited a proteomic remodeling of complex I and III, mitochondria from AE-PKCε exhibited an increased expression of multiple subunits, including the catalytic complex III subunit Cyc1. This finding was accompanied by a preserved complex III activity (p<0.05), as well as tempered superoxide production (p<0.01) subsequent to Ca2+-induced damage. This is the first study documenting a salutary proteomic remodeling of the mitochondrial respiratory machinery in cardioprotection. Quantitative proteomics technology enabled novel information and new insights into mitochondrial biology.

ROS-Induced DNA Damage Causing Genomic Instability in CML Stem and/or Progenitor Cells and in Quiescent and/or Proliferating Cells: Role of Mitochondrial Respiratory Chain Complex III.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3268-3268
Author(s):  
Margaret Nieborowska-Skorska ◽  
Mateusz Koptyra ◽  
Elisabeth Bolton ◽  
Regina Ray ◽  
Danielle Ngaba ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Respiratory Chain ◽  
Chromosomal Aberrations ◽  
Oxidative Dna Damage ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Abl Kinase ◽  
Mitochondrial Respiratory

Abstract Abstract 3268 Poster Board III-1 BCR/ABL kinase transforms hematopoietic stem cells to induce chronic myelogenous leukemia (CML). CML in chronic phase (CML-CP) is a leukemia stem cell (LSC)-derived but leukemia progenitor cell (LPC)-driven disease, which is, in most cases, sensitive to ABL tyrosine kinase inhibitors (TKIs) monotherapy. TKIs do not eradicate the leukemia but instead usually render the disease ‘inactive', since the residual quiescent LSCs are intrinsically insensitive to BCR-ABL inhibition and, in a significant cohort of CML patients, LPCs are also refractory or acquire resistance to TKIs due to mutations in BCR/ABL kinase. In the post-imatinib era, these cells may eventually undergo transformation and initiate fatal CML blast crisis (CML-BC). The malignant progression is usually associated with enhanced expression of BCR/ABL and accumulation of additional genetic aberrations, such as TKI-resistant mutations and chromosomal aberrations. In CML-CP, LSCs and LPCs reside in the CD34+CD38- and CD34+CD38+ populations, respectively, whereas in CML-BC, LSCs are also found in the CD34+CD38+ population. In addition, LSCs and LPCs usually belong to quiescent (CFSEmax) and proliferative (CFSElow) populations, respectively. However, the origin of CML-BC clone and the role of BCR/ABL “dosage” are not known. Since genomic instability usually results from DNA damage, we investigated the mechanisms responsible for enhanced DNA damage in CML cells. Much endogenous DNA damage arises from free radicals such as reactive oxygen species (ROS). Here we show that LSCs-enriched CD34+CD38- and quiescent (CFSEmax) CML cells and LPCs-enriched CD34+CD38+ cells contain higher levels of ROS (superoxide anion, hydrogen peroxide, and hydroxyl radical) than corresponding cells from normal donors (CML-BC>CML-CP>Normal). Interestingly, CFSEmax and CFSElow CML cells displayed similar elevation of ROS indicating that the presence of BCR/ABL and not the proliferative status enhances ROS. In addition, total cellular ROS and mitochondrial ROS levels were proportional to the expression of BCR/ABL kinase implicating the role of BCR/ABL kinase “dosage”. Higher levels of ROS caused more oxidative DNA lesions, such as 8-oxoG and DNA double-strand breaks (DSBs) in CD34+ and also in CD34+CD38- CML cells than in normal counterparts (CML-BC>CML-CP>Normal). Inhibition of BCR/ABL kinase with imatinib partially reduced ROS and oxidative DNA damage in CD34+ CML-CP cells, implicating BCR/ABL-dependent and -;independent mechanisms. Our previous studies showed that elevated levels of oxidative DNA damage in BCR/ABL-transformed cells were responsible for accumulation of TKI-resistant BCR/ABL mutants and chromosomal aberrations (Blood, 2006; Leukemia, 2008), highlighting the importance of identification of the sources of ROS in CML. Mitochondrial respiratory chain (MRC) is a major site of ATP production via oxidative phosphorylation, which is associated with electron flux through MRC. Some of the electrons may escape and react with molecular oxygen to form ROS. To shut down MRC, cells were depleted of mitochondrial DNA (mtDNA) by long-term exposure to ethidium bromide in the presence of uridine and pyruvate as confirmed by RT-PCR showing the absence/reduction of mtDNA-coded Cox II gene transcript. The absence of functional MRC reduced the level of ROS by 40% and 20% in CD34+ CML-CP cells and normal counterparts, respectively, suggesting that MRC is an important source of ROS in leukemia cells. Using selective inhibitors of various MRC complexes we identified complex III as major producer of ROS in LSCs and LPCs in CML-CP. The role of complex III in CML-BC cells is somehow diminished in concordance with the observation that prolonged exposure of MRC to elevated levels of ROS results in “mitochondrial injury” and reduction of MRC activity in advanced stages of cancer. In summary, we postulate that BCR/ABL kinase generates ROS and oxidative DNA damage in a dose-dependent manner not only in LPCs-enriched CD34+CD38+ and CFSElow cells, but also in LSCs-enriched CD34+CD38- and CFSEmax cells, and that MRC complex III generates significant amount of ROS in CML-CP cells. Thus, genomic instability causing TKI resistance and progression to CML-BC may originate in LSCs as well as in LPCs. Disclosures: No relevant conflicts of interest to declare.

Evaluation of energetic metabolism in the rat brain after meningitis induction byKlebsiella pneumoniae

2013 ◽  
Vol 25 (2) ◽  
pp. 95-100 ◽  
Author(s):  
Tatiana Barichello ◽  
Lutiana Roque Simões ◽  
Jaqueline S. Generoso ◽  
Mirelle M. Carradore ◽  
Ana Paula Moreira ◽  
...  
Keyword(s):  
Antibiotic Treatment ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Wistar Rat ◽  
High Energy ◽  
Complex Iii ◽  
Respiratory Chain Complexes ◽  
Sterile Saline ◽  
Cell Energy ◽  
Mitochondrial Respiratory

BackgroundBacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy.ObjectivesEvaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis byKlebsiella pneumoniae.MethodsAdult Wistar rats received either 10 µl of sterile saline as a placebo or an equivalent volume ofK. pneumoniaesuspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction.ResultsIn the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration.DiscussionAlthough descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of theK. pneumoniaemeningitis.

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