Revisiting Kadenbach: Electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS

The function of the nonreceptor tyrosine kinase c-Src as a plasma membrane–associated molecular effector of a variety of extracellular stimuli is well known. Here, we show that c-Src is also present within mitochondria, where it phosphorylates cytochrome c oxidase (Cox). Deleting the c-src gene reduces Cox activity, and this inhibitory effect is restored by expressing exogenous c-Src. Furthermore, reducing endogenous Src kinase activity down-regulates Cox activity, whereas activating Src has the opposite effect. Src-induced Cox activity is required for normal function of cells that require high levels of ATP, such as mitochondria-rich osteoclasts. The peptide hormone calcitonin, which inhibits osteoclast function, also down-regulates Cox activity. Increasing Src kinase activity prevented the inhibitory effect of calcitonin on Cox activity and osteoclast function. These results suggest that c-Src plays a previously unrecognized role in maintaining cellular energy stores by activating Cox in mitochondria.

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VO2 Kinetics in Supra-Anaerobic Threshold Constant Tests Allow the Visualization and Quantification of the O2 Saving After Cytochrome C Oxidase Inhibition by Aerobic Training or Nitrate Administration

Physiological Research ◽

10.33549/physiolres.932484 ◽

2013 ◽

pp. 671-679

Author(s):

D. MAIONE ◽

A. F. G. CICERO ◽

S. BACCHELLI ◽

E. COSENTINO ◽

D. DEGLI ESPOSTI ◽

...

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Anaerobic Threshold ◽

Aerobic Training ◽

Inhibitory Effect ◽

Constant Load ◽

Cycle Ergometer ◽

No Donor ◽

Vo2 Kinetics ◽

Oxidase Inhibition

We tested whether the known cytochrome c oxidase (COX) inhibition by nitric oxide (NO) could be quantified by VO2 kinetics during constant load supra-Anaerobic Threshold (AT) exercises in healthy trained or untrained subjects following aerobic training or nitrate administration. In cycle ergometer constant load exercises supra-AT, identified in previous incremental tests, VO2 kinetics describe a double exponential curve, one rapid and one appreciably slower, allowing the area between them to be calculate in O2 l. After training, with increased NO availability, this area decreases in inverse ratio to treatment efficacy. In fact, in 11 healthy subjects after aerobic training for 6-7 weeks, area was decreased on average by 51 %. In 11 untrained subjects, following the assumption of an NO donor, 20 mg isosorbide 5 mononitrate, area was decreased on average by 53 %. In conclusion, supra-AT VO2 kinetics in constant load exercises permit the quantification of the inhibitory effect NO-dependent on COX after either physical training or nitrate assumption.

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Regulation of electron flux through cytochrome c oxidase: pH, ΔpH and fatty acids

Biochemical Society Transactions ◽

10.1042/bst0210781 ◽

1993 ◽

Vol 21 (3) ◽

pp. 781-784 ◽

Cited By ~ 2

Author(s):

John M. Wrigglesworth ◽

Martyn A. Sharpe ◽

Chris E. Cooper

Keyword(s):

Fatty Acids ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Electron Flux

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Oxytetracycline inhibition of mitochondrial protein synthesis in bovine lymphocytes infected withTheileria parvaor stimulated by mitogen

Parasitology ◽

10.1017/s0031182000060583 ◽

1990 ◽

Vol 101 (3) ◽

pp. 387-393 ◽

Cited By ~ 6

Author(s):

P. R. Spooner

Keyword(s):

Protein Synthesis ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Oxidase Activity ◽

Mitochondrial Protein ◽

Inhibitory Effect ◽

Mitochondrial Protein Synthesis ◽

Drug Concentrations ◽

Bovine Lymphocytes

SUMMARYOxytetracycline (OTC) significantly inhibited cytochrome c oxidase activity in bovine lymphocytes infected withTheileria parvaand in uninfected mitogen-stimulated lymphocytes. The inhibitory effect was detectedin vitrowithin 24 h of treatment with drug concentrations as low as 1 µg/ml. Following mitogen stimulation of lymphocytes, concentrations of 3 and 10 µg/ml OTC completely inhibited an increase in cytochrome c oxidase activity for 48–72 h. This inhibitory activity was considered to be due to a direct effect on lymphoblast mitochondrial protein synthesis. As a consequence, adenosine triphosphate activity was significantly reduced in lymphocytes stimulated either by infection withT. parvasporozoites or by mitogen and then treated with OTC. The results also indicated that parasite mitochondrial protein synthesis was inhibited by OTC. The activity of OTC reported in this study could explain the suppression of disease following ‘infection and treatment’ immunization against East Coast fever and thein vitrodrug-inhibition of schizont development.

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