Palmitate decreases proton pumping of liver‐type cytochrome <i>c</i> oxidase

Lee, Icksoo; Kadenbach, Bernhard

doi:10.1046/j.0014-2956.2001.02602.x

Cited by 39 publications

(14 citation statements)

References 31 publications

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“…Subunit VIa isoforms have also been shown to respond to high ATP/ADP ratios. Binding of ATP to the heart and skeletal muscle isoform, VIaH, reduces the proton to electron stoichiometric ratio (48), and binding of palmitate to the liver isoform, VIaL, has a comparable effect (49). Subunit VIb, in addition to subunits III, Vb, and VIa, provides unique contact sites between the two monomers of COX.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2008

Journal of Biological Chemistry

146

188

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Cytochrome c oxidase (COX) is one of only four bigenomic proteins in mammalian cells, having ten subunits encoded in the nuclear genome and three in the mitochondrial DNA. The mechanism of its bigenomic control is not well understood. The ten nuclear subunits are on different chromosomes, and the possibility of their coordinate regulation by the same transcription factor(s) deserves serious consideration. The present study tested our hypothesis that nuclear respiratory factor 1 (NRF-1) serves such a role in subunit coordination. Following in silico analysis of murine nuclear-encoded COX subunit promoters, electrophoretic mobility shift and supershift assays indicated NRF-1 binding to all ten promoters. In vivo chromatin immunoprecipitation assays also showed NRF-1 binding to all ten promoters in murine neuroblastoma cells. Site-directed mutagenesis of putative NRF-1 binding sites confirmed the functionality of NRF-1 binding on all ten COX promoters. These sites are highly conserved among mice, rats, and humans. Silencing of NRF-1 with RNA interference reduced all ten COX subunit mRNAs and mRNAs of other genes involved in mitochondrial biogenesis. We conclude that NRF-1 plays a significant role in coordinating the transcriptional regulation of all ten nuclearencoded COX subunits in neurons. Moreover, NRF-1 is known to activate mitochondrial transcription factors A and B, thereby indirectly regulating the expressions of the three mitochondrial-encoded COX subunits. Thus, NRF-1 and our previously described NRF-2 prove to be the two key bigenomic coordinators for transcriptional regulation of all cytochrome c oxidase subunits in neurons. Possible interactions between the NRFs will be investigated in the future.Cytochrome c oxidase or complex IV is a large transmembrane protein located in the inner mitochondrial membrane of eukaryotes and plasma membrane of prokaryotes. It is the terminal enzyme of the electron transport chain, catalyzing the transfer of electrons from reduced cytochrome c to molecular oxygen to form water. The important outcome of this reaction is the generation of ATP through the coupled process of oxidative phosphorylation. Neurons are highly dependent upon ATP for their activity and functions (1). Approximately 90% of ATP generated in the brain is synthesized in the mitochondria via oxidative phosphorylation (2). The activity of this enzyme is reduced in neurodegenerative diseases, such as Alzheimer disease (3, 4). Among respiratory chain deficiencies presented in infancy and early childhood in humans, cytochrome c oxidase (COX) 2 deficiency is the most commonly diagnosed (5). COX deficiency is found with different clinical phenotypes primarily affecting organs with high energy demand, such as the brain, skeletal muscle, heart, and kidney (6).COX is a complex of 13 different subunits, 3 of which (I, II, and III) are encoded in the mitochondrial DNA, and the remaining 10 are nuclear-encoded (7). To form a functional holoenzyme with 1:1 stoichiometry, exact coordination is essential between the two...

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Section: Discussionmentioning

confidence: 99%

Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2008

Journal of Biological Chemistry

146

188

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“…In cytochrome c oxidase from all other tissues (subunit VIaL) the H + /e -stoichiometry decreases from 1.0 to 0.5 specifically in the presence of palmitate with halfmaximal extent at 0.5 µM (Lee and Kadenbach, 2001). The previously described H + /e -stoichiometry of 0.5 in the enzymes from bovine liver and kidney and turkey liver and heart , all containing subunit VIaL, increases to 1.0 by including cardiolipin during reconstitution (Lee and Kadenbach, 2001). The palmitate effect could participate in maintaining constant body temperature and control of obesity.…”

Section: Why Are Two Mechanisms Of Respiratory Control Required?mentioning

confidence: 97%

New Control of Mitochondrial Membrane Potential and ROS Formation A Hypothesis

Lee

Bender²,

Arnold³

et al. 2001

Biological Chemistry

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A new control of mitochondrial membrane potential delta(psi)m and formation of reactive oxygen species (ROS) is presented, based on allosteric ATP-inhibition of cytochrome c oxidase at high intramitochondrial ATP/ADP ratios. Since the rate of ATP synthesis by the ATP synthase is already maximal at low membrane potentials (100-120 mV), the ATP/ADP ratio will also be maximal at this delta(psi)m (at constant rate of ATP consumption). Therefore the control of respiration by the ATP/ADP-ratio keeps delta(psi)m low. In contrast, the known 'respiratory control' leads to an inhibition of respiration only at high delta(psi)m values (150-200 mV) which cause ROS formation. ATP-inhibition of cytochrome c oxidase is switched on and off by reversible phosphorylation (via cAMP and calcium, respectively). We propose that 'stress hormones' which increase intracellular [Ca2+] also increase delta(psi)m and ROS formation, which promote degenerative diseases and accelerate aging.

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“…Conversely, COX possessing the heart-type paralog (COX6A-2) is able to adjust the COX H + /e − ratio from 0.5 to 1.0 in response to an increase in the ATP/ADP ratio (Frank and Kadenbach 1996). The ability of a cell to alter proton-pumping efficiency by changing paralogs or introducing an ability to respond to energy status has been hypothesized to be important in thermogenic strategies by uncoupling COX activity from ATP production (Hüttemann et al 1999;Lee and Kadenbach 2001). If the evolution of COX6A is indeed linked to homeothermy, it is noteworthy that birds possess only one paralog for COX6A.…”

Section: Paralogs Of Cox Subunitsmentioning

confidence: 98%

Energy metabolism and cytochrome oxidase activity: linking metabolism to gene expression

Bremer

SniderT.

2014

Can. J. Zool.

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Modification of mitochondrial content demands the synthesis of hundreds of proteins encoded by nuclear and mitochondrial genomes. The responsibility for coordination of this process falls to nuclear-encoded master regulators of transcription. DNAbinding proteins and coactivators integrate information from energy-sensing pathways and hormones to alter mitochondrial gene expression. In mammals, the signaling cascade for mitochondrial biogenesis can be described as follows: hormonal signals and energetic information are sensed by protein-modifying enzymes that in turn regulate the post-translational modification of transcription factors. Once activated, transcription-factor complexes form on promoter elements of many of the nuclear-encoded mitochondrial genes, recruiting proteins that remodel chromatin and initiate transcription. One master regulator in mammals, PGC-1␣, is well studied because of its role in determining the metabolic phenotype of muscles, but also due to its importance in mitochondria-related metabolic diseases. However, relatively little is known about the role of this pathway in other vertebrates. These uncertainties raise broader questions about the evolutionary origins of the pathway and its role in generating the diversity in muscle metabolic phenotypes seen in nature.Résumé : La modification du contenu mitochondrial nécessite la synthèse de centaines de protéines encodées par les génomes nucléaire et mitochondrial, la coordination de ce processus étant assurée par des maîtres régulateurs de la transcription codés par le génome nucléaire. Des protéines se liant à l'ADN et des coactivateurs intègrent l'information provenant de voies de détection de l'énergie et d'hormones pour ensuite modifier l'expression des gènes mitochondriaux. Chez les mammifères, la cascade de signalisation pour la biogénèse mitochondriale peut être décrite comme suit : des enzymes de modification de protéines détectent des signaux hormonaux et de l'information énergétique et régulent la modification post-traduction des facteurs de transcription. Une fois activés, des complexes de facteurs de transcription se forment sur des éléments promoteurs de nombreux gènes mitochondriaux à encodage nucléaire, recrutant des protéines qui remodèlent la chromatine et amorcent la transcription. Un des maîtres régulateurs chez les mammifères, le PGC-1␣, fait l'objet de nombreuses études en raison de son rôle dans la détermination du phénotype métabolique des muscles, mais aussi en raison de son importance dans les maladies métaboliques associées aux mitochondries. Les connaissances sur le rôle de cette voie chez d'autres vertébrés sont toutefois limitées. Ces incertitudes soulèvent des questions plus larges concernant les origines évolutives de cette voie et son rôle dans la production de la diversité de phénotypes métaboliques musculaires observée dans la nature. [Traduit par la Rédaction]

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Palmitate decreases proton pumping of liver‐type cytochrome c oxidase

Cited by 39 publications

References 31 publications

Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

New Control of Mitochondrial Membrane Potential and ROS Formation A Hypothesis

Energy metabolism and cytochrome oxidase activity: linking metabolism to gene expression

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