Bernhard Kadenbach

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Organization: University of Marburg , Germany

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Title: (PhD)

Chemicals
References

Regulation of Mammalian 13-Subunit Cytochrome c Oxidase and Binding of other Proteins: Role of NDUFA4

Co-reporter:Bernhard Kadenbach

Trends in Endocrinology & Metabolism 2017 Volume 28, Issue 11(Issue 11) pp:

Publication Date(Web):1 November 2017

DOI:10.1016/j.tem.2017.09.003

Cytochrome c oxidase (CcO) is the final oxygen accepting enzyme complex (complex IV) of the mitochondrial respiratory chain. In contrast to the other complexes (I, II, and III), CcO is highly regulated via isoforms for six of its ten nuclear-coded subunits, which are differentially expressed in species, tissues, developmental stages, and cellular oxygen concentrations. Recent publications have claimed that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4), originally identified as subunit of complex I, represents a 14th subunit of CcO. Results on CcO composition in tissues from adult animals and the review of data from recent literature strongly suggest that NDUFA4 is not a 14th subunit of CcO but may represent an assembly factor for CcO or supercomplexes (respirasomes) in mitochondria of growing cells and cancer tissues.

Der Mensch, ein elektrisches Wesen : Biochemie

Co-reporter: Bernhard Kadenbach

Chemie in unserer Zeit 2015 Volume 49( Issue 5) pp:330-335

Publication Date(Web):

DOI:10.1002/ciuz.201500693

Abstract

Unser Körper besteht aus Zellen, die, wie auch die Organellen im Innern der Zellen von einer biologischen Membran umgeben sind. Diese besteht aus einer Lipiddoppelschicht, die für den elektrischen Strom undurchlässig ist. Über den meisten Membranen lebender Zellen liegt eine elektrische Spannung, bzw. ein elektrochemisches Potential. Alle Lebensäußerungen des Menschen erfordern Energie, die vor allem durch das Molekül ATP bereitgestellt wird. Die chemische Energie im ATP stammt aus der “kalten Verbrennung” unserer Nährstoffe in den Mitochondrien, wobei intermediär ein elektrochemisches Potential an der Innenmembran der Mitochondrien entsteht. Die ATP-Synthase nutzt die Energie dieses Potentials zur Bildung von ATP. Übersteigt die Spannung einen bestimmten Wert, so bilden sich schädliche Sauerstoffradikale. Hohe ATP-Gehalte in Mitochondrien verhindern die Bildung der Sauerstoffradikale durch Hemmung der Cytochrom-c-Oxidase, dem letzten Glied der Zellatmung. Bei Stresssituationen des Organismus wird diese ATP-Hemmung aufgehoben, wodurch die Spannung ansteigt und Sauerstoffradikale entstehen, die als Ursache für zahlreiche Krankheiten gelten.

The cells of our body, and the organelles within the cells, are surrounded by a biological membrane. The membranes are composed of a lipid bilayer which has no conductivity for the electric current. Across most biological membranes of living cells exists an electric tension or an electrochemical potential. All expressions of human life require energy which is supplied by the molecule ATP. The chemical energy of ATP originates from “cold combustion" of nutrients in mitochondria, accompanied by the intermediate formation of an electrochemical potential. The ATP-synthase uses the energy of the potential to form ATP. If the tension across the membrane exceeds a certain value, deleterious oxygen radicals are formed. High ATP-values prevent the formation of oxygen radicals by inhibition of cytochrome c oxidase, the last step of cell respiration. During stress situations of the organism this ATP-inhibition is switched off so that the electric tension increases and oxygen radicals are produced. These have been shown to cause multiple degenerative diseases.

The subunit composition and function of mammalian cytochrome c oxidase

Co-reporter:Bernhard Kadenbach, Maik Hüttemann

Mitochondrion (September 2015) Volume 24() pp:64-76

Publication Date(Web):1 September 2015

DOI:10.1016/j.mito.2015.07.002

•Mammalian cytochrome c oxidase (COX) contains 13 subunits, not 14 subunits as proposed by Balsa et al., 2012.•The function is described for some subunits. No specific function is known for subunits VIb, VIc, VIIa, VIIb, VIIc, and VIII.•Phosphorylation of COX is described which has a strong influence on mitochondrial respiration.•Diseases based on mutations in mitochondria- or nuclear-coded subunits and in assembly factors for COX are discussed.Cytochrome c oxidase (COX) from mammals and birds is composed of 13 subunits. The three catalytic subunits I-III are encoded by mitochondrial DNA, the ten nuclear-coded subunits (IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIII) by nuclear DNA. The nuclear-coded subunits are essentially involved in the regulation of oxygen consumption and proton translocation by COX, since their removal or modification changes the activity and their mutation causes mitochondrial diseases. Respiration, the basis for ATP synthesis in mitochondria, is differently regulated in organs and species by expression of tissue-, developmental-, and species-specific isoforms for COX subunits IV, VIa, VIb, VIIa, VIIb, and VIII, but the holoenzyme in mammals is always composed of 13 subunits. Various proteins and enzymes were shown, e.g., by co-immunoprecipitation, to bind to specific COX subunits and modify its activity, but these interactions are reversible, in contrast to the tightly bound 13 subunits. In addition, the formation of supercomplexes with other oxidative phosphorylation complexes has been shown to be largely variable. The regulatory complexity of COX is increased by protein phosphorylation. Up to now 18 phosphorylation sites have been identified under in vivo conditions in mammals. However, only for a few phosphorylation sites and four nuclear-coded subunits could a specific function be identified. Research on the signaling pathways leading to specific COX phosphorylations remains a great challenge for understanding the regulation of respiration and ATP synthesis in mammalian organisms. This article reviews the function of the individual COX subunits and their isoforms, as well as proteins and small molecules interacting and regulating the enzyme.

The role of mitochondrial membrane potential in ischemic heart failure

Co-reporter:Bernhard Kadenbach, Rabia Ramzan, Rainer Moosdorf, Sebastian Vogt

Mitochondrion (September 2011) Volume 11(Issue 5) pp:700-706

Publication Date(Web):1 September 2011

DOI:10.1016/j.mito.2011.06.001

The molecular events occurring during myocardial infarction and cardioprotection are described with an emphasis on the changes of the mitochondrial membrane potential (ΔΨm). The low ΔΨm values of the normal beating heart (100–140 mV) are explained by the allosteric ATP-inhibition of cytochrome c oxidase (CcO) through feedback inhibition by ATP at high [ATP]/[ADP] ratios. During ischemia the mechanism is reversibly switched off by signaling through reactive oxygen species (ROS). At reperfusion high ΔΨm values cause a burst of ROS production leading to apoptosis and/or necrosis. Ischemic preconditioning is suggested to cause additional phosphorylation of CcO, protecting the enzyme from immediate dephosphorylation via ROS signaling.

High efficiency versus maximal performance — The cause of oxidative stress in eukaryotes: A hypothesis

Co-reporter:Bernhard Kadenbach, Rabia Ramzan, Sebastian Vogt

Mitochondrion (January 2013) Volume 13(Issue 1) pp:1-6

Publication Date(Web):1 January 2013

DOI:10.1016/j.mito.2012.11.005

Degenerative diseases are in part based on elevated production of ROS (reactive oxygen species) in mitochondria, mainly during stress and excessive work under stress (strenuous exercise). The production of ROS increases with increasing mitochondrial membrane potential (ΔΨm). A mechanism is described which is suggested to keep ΔΨm at low values under normal conditions thus preventing ROS formation, but is switched off under stress and excessive work to maximize the rate of ATP synthesis, accompanied by decreased efficiency. Low ΔΨm and low ROS production are suggested to occur by inhibition of respiration at high [ATP]/[ADP] ratios. The nucleotides interact with phosphorylated cytochrome c oxidase (COX), representing the step with the highest flux-control coefficient of mitochondrial respiration. At stress and excessive work neural signals are suggested to dephosphorylate the enzyme and abolish the control of COX activity (respiration) by the [ATP]/[ADP] ratio with consequent increase of ΔΨm and ROS production. The control of COX by the [ATP]/[ADP] ratio, in addition, is proposed to increase the efficiency of ATP production via a third proton pumping pathway, identified in eukaryotic but not in prokaryotic COX. We conclude that ‘oxidative stress’ occurs when the control of COX activity by the [ATP]/[ADP] ratio is switched off via neural signals.Highlights► A mechanism is described which prevents high ΔΨm and ROS formation in cells ► High ROS in living cells (oxidative stress) leads to aging and degenerative diseases ► The mechanism is switched on by phosphorylation of cytochrome c oxidase (COX) ► It is switched off under stress or excessive work by dephosphorylation of COX ► High efficiency of ATP synthesis occurs at low ΔΨm by increased H+/e − ratio in COX

Degenerative diseases, oxidative stress and cytochrome c oxidase function

Co-reporter:Bernhard Kadenbach, Rabia Ramzan, Sebastian Vogt

Trends in Molecular Medicine (April 2009) Volume 15(Issue 4) pp:139-147

Publication Date(Web):1 April 2009

DOI:10.1016/j.molmed.2009.02.004

Aging and degenerative diseases are associated with increased levels of reactive oxygen species (ROS). ROS are mostly produced in mitochondria, and their levels increase with higher mitochondrial membrane potential. Cellular respiratory control is based on inhibition of respiration by high membrane potentials. However, we have described a second mechanism of respiratory control based on allosteric inhibition of cytochrome c oxidase (CcO), the terminal enzyme of the respiratory chain, at high ATP:ADP ratios. The mechanism is independent of membrane potential. We have proposed that feedback inhibition of CcO by ATP keeps the membrane potential and ROS production at low levels. Various forms of stress switch off allosteric ATP-inhibition via reversible dephosphorylation of CcO, resulting in increased membrane potential and cellular ROS levels. This mechanism is proposed to represent a missing molecular link between stress and degenerative diseases.