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An in situ study of bioenergetic properties of human colorectal cancer: The regulation of mitochondrial respiration and distribution of flux control among the components of ATP synthasome |
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| Institution: | 1. College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan, ROC;2. National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan, ROC;3. Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan, ROC;4. School of Dental Technology, Taipei Medical University, Taipei, Taiwan, ROC;5. Department of Materials Science and Engineering, National Chiao Tung University, Hsin-Chu, Taiwan, ROC |
| Abstract: | The aim of this study is to characterize the function of mitochondria and main energy fluxes in human colorectal cancer (HCC) cells. We have performed quantitative analysis of cellular respiration in post-operative tissue samples collected from 42 cancer patients. Permeabilized tumor tissue in combination with high resolution respirometry was used.Our results indicate that HCC is not a pure glycolytic tumor and the oxidative phosphorylation (OXPHOS) system may be the main provider of ATP in these tumor cells. The apparent Michaelis–Menten constant (Km) for ADP and maximal respiratory rate (Vm) values were calculated for the characterization of the affinity of mitochondria for exogenous ADP: normal colon tissue displayed low affinity (Km = 260 ± 55 μM) whereas the affinity of tumor mitochondria was significantly higher (Km = 126 ± 17 μM). But concurrently the Vm value of the tumor samples was 60–80% higher than that in control tissue. The reason for this change is related to the increased number of mitochondria. Our data suggest that in both HCC and normal intestinal cells tubulin β-II isoform probably does not play a role in the regulation of permeability of the MOM for adenine nucleotides.The mitochondrial creatine kinase energy transfer system is not functional in HCC and our experiments showed that adenylate kinase reactions could play an important role in the maintenance of energy homeostasis in colorectal carcinomas instead of creatine kinase.Immunofluorescent studies showed that hexokinase 2 (HK-2) was associated with mitochondria in HCC cells, but during carcinogenesis the total activity of HK did not change. Furthermore, only minor alterations in the expression of HK-1 and HK-2 isoforms have been observed.Metabolic Control analysis showed that the distribution of the control over electron transport chain and ATP synthasome complexes seemed to be similar in both tumor and control tissues. High flux control coefficients point to the possibility that the mitochondrial respiratory chain is reorganized in some way or assembled into large supercomplexes in both tissues. |
| Keywords: | Energy metabolism Metabolic control analysis Colorectal cancer Mitochondria VDAC Hexokinase Tubulin Warburg effect AK"} {"#name":"keyword" "$":{"id":"kw0050"} "$$":[{"#name":"text" "_":"adenylate kinase ANT"} {"#name":"keyword" "$":{"id":"kw0060"} "$$":[{"#name":"text" "_":"adenine nucleotide translocator BSA"} {"#name":"keyword" "$":{"id":"kw0070"} "$$":[{"#name":"text" "_":"bovine serum albumin CAT"} {"#name":"keyword" "$":{"id":"kw0080"} "$$":[{"#name":"text" "_":"carboxyatractyloside COX"} {"#name":"keyword" "$":{"id":"kw0090"} "$$":[{"#name":"text" "_":"cytochrome c oxidase CK"} {"#name":"keyword" "$":{"id":"kw0100"} "$$":[{"#name":"text" "_":"creatine kinase ETC"} {"#name":"keyword" "$":{"id":"kw0110"} "$$":[{"#name":"text" "_":"electron transport chain FDG"} {"#name":"keyword" "$":{"id":"kw0120"} "$$":[{"#name":"text" "_":"18-fluorodeoxyglucose FCC"} {"#name":"keyword" "$":{"id":"kw0130"} "$$":[{"#name":"text" "_":"flux control coefficient HCC"} {"#name":"keyword" "$":{"id":"kw0140"} "$$":[{"#name":"text" "_":"human colorectal cancer HK"} {"#name":"keyword" "$":{"id":"kw0150"} "$$":[{"#name":"text" "_":"hexokinase Michaelis–Menten constant uMtCK"} {"#name":"keyword" "$":{"id":"kw0170"} "$$":[{"#name":"text" "_":"ubiquitous mitochondrial creatine kinase MCA"} {"#name":"keyword" "$":{"id":"kw0180"} "$$":[{"#name":"text" "_":"Metabolic Control Analysis 3-NP"} {"#name":"keyword" "$":{"id":"kw0190"} "$$":[{"#name":"text" "_":"3-nitropropionic acid OXPHOS"} {"#name":"keyword" "$":{"id":"kw0200"} "$$":[{"#name":"text" "_":"oxidative phosphorylation MOM"} {"#name":"keyword" "$":{"id":"kw0210"} "$$":[{"#name":"text" "_":"mitochondrial outer membrane PCr"} {"#name":"keyword" "$":{"id":"kw0220"} "$$":[{"#name":"text" "_":"phosphocreatine PET"} {"#name":"keyword" "$":{"id":"kw0230"} "$$":[{"#name":"text" "_":"positron emission tomography Pi"} {"#name":"keyword" "$":{"id":"kw0240"} "$$":[{"#name":"text" "_":"inorganic phosphate PIC"} {"#name":"keyword" "$":{"id":"kw0250"} "$$":[{"#name":"text" "_":"inorganic phosphate carrier PEP"} {"#name":"keyword" "$":{"id":"kw0260"} "$$":[{"#name":"text" "_":"phosphoenolpyruvate PYK"} {"#name":"keyword" "$":{"id":"kw0270"} "$$":[{"#name":"text" "_":"pyruvate kinase RCI"} {"#name":"keyword" "$":{"id":"kw0280"} "$$":[{"#name":"text" "_":"respiratory control index TMPD"} {"#name":"keyword" "$":{"id":"kw0290"} "$$":[{"#name":"text" "_":"N N N′ N′-tetramethyl-p-phenylenediamine VDAC"} {"#name":"keyword" "$":{"id":"kw0300"} "$$":[{"#name":"text" "_":"voltage dependent anion channel basal respiration level maximal respiration rate |
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