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. 2020 Mar 28;12(4):815.
doi: 10.3390/cancers12040815.

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

Free PMC article

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

Egle Rebane-Klemm et al. Cancers (Basel). .
Free PMC article


This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: KRAS mutated, BRAF mutated and KRAS/BRAF wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (Vmax) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. KRAS mutated CRC group had lower Vmax values compared to wild-type; however, the Vmax value was higher than in the control group, while MOM permeability did not change. This suggests that KRAS mutation status might be involved in acquiring oxidative phenotype. KRAS mutated polyps had higher Vmax values and elevated MOM permeability as compared to the control. BRAF mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification.

Keywords: BRAF; KRAS; colorectal cancer; colorectal polyps; energy metabolism; mitochondria; oxidative phosphorylation.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.


Figure 1
Figure 1
Regulation of mitochondrial respiration in KRAS+, BRAF+ and wild-type tumors and control. (A) Comparative analysis of maximal ADP-activated respiratory rate (Vmax) and (B) the apparent Michaelis–Menten constant (Km(ADP)) values for ADP. KRAS+: KRAS mutated; BRAF+: BRAF mutated; WT: wild type; CRC: colorectal cancer; Control: control tissue. * p < 0.05; ** p < 0.01.
Figure 2
Figure 2
(A) In the current study, a comparison of all distal and proximal tumors showed a difference in Km(ADP) values, but not in Vmax. (B) Vmax and Km(ADP) values comparing proximal and distal tumors in the KRAS mutated group. ** Significant difference, p < 0.01.
Figure 3
Figure 3
Different kinetics of regulation of mitochondrial respiration by exogenous ADP in colon tissue. (A) Recording of original traces of O2 consumption by permeabilized colorectal cancer (CRC) tissue upon additions of increasing concentrations of ADP. CAT stands for carboxyatractyloside; CyoC stands for cytochrome C. (B) The measured respiration rates were plotted vs ADP concentrations, and from this plot corresponding Vmax and Km(ADP) values were calculated by nonlinear regression using Michaelis–Menten equation. There was a marked difference in ADP kinetics between wild-type CRC, colon polyps and normal colon tissue (control).

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