title: Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer.
abstract: The aim of this study was to analyze quantitatively cellular respiration in intraoperational tissue samples taken from human breast cancer (BC) patients. We used oxygraphy and the permeabilized cell techniques in combination with Metabolic Control Analysis (MCA) to measure a corresponding flux control coefficient (FCC). The activity of all components of ATP synthasome, and respiratory chain complexes was found to be significantly increased in human BC cells in situ as compared to the adjacent control tissue. FCC(s) were determined upon direct activation of respiration with exogenously-added ADP and by titrating the complexes with their specific inhibitors to stepwise decrease their activity. MCA showed very high sensitivity of all complexes and carriers studied in human BC cells to inhibition as compared to mitochondria in normal oxidative tissues. The sum of FCC(s) for all ATP synthasome and respiratory chain components was found to be around 4, and the value exceeded significantly that for normal tissue (close to 1). In BC cells, the key sites of the regulation of respiration are Complex IV (FCC = 0.74), ATP synthase (FCC = 0.61), and phosphate carrier (FCC = 0.60); these FCC(s) exceed considerably (~10-fold) those for normal oxidative tissues. In human BC cells, the outer mitochondrial membrane is characterized by an increased permeability towards adenine nucleotides, the mean value of the apparent K(m) for ADP being equal to 114.8 ± 13.6 μM. Our data support the two-compartment hypothesis of tumor metabolism, the high sum of FCC(s) showing structural and functional organization of mitochondrial respiratory chain and ATP synthasome as supercomplexes in human BC.
authors: Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Estonia. tuuli.kaambre@kbfi.ee
authors: Tuuli
authors: T
authors: Kaambre
authors: Vladimir
authors: V
authors: Chekulayev
authors: Igor
authors: I
authors: Shevchuk
authors: Minna
authors: M
authors: Karu-Varikmaa
authors: Natalja
authors: N
authors: Timohhina
authors: Kersti
authors: K
authors: Tepp
authors: Jelena
authors: J
authors: Bogovskaja
authors: Riina
authors: R
authors: Kütner
authors: Vahur
authors: V
authors: Valvere
authors: Valdur
authors: V
authors: Saks
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010101:Oxygen Consumption
chemical_list: D045222:Electron Transport Chain Complex Proteins; D009363:Neoplasm Proteins; D000255:Adenosine Triphosphate