A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase

Abstract

An increasing number of cancer types have been found to be linked to specific mutations in the mitochondrial DNA, which result in specific structural changes of the respiratory enzyme complexes. In this study, we have investigated the effect of 2 such mutations identified in colon cancer patients, leading to the amino acid substitutions Ser458Pro and Gly125Asp in subunit I of cytochrome c oxidase (complex IV) [Greaves et al. (2006) Proc Natl Acad Sci USA 103:714 -719]. We introduced these mutations in Rhodobacter sphaeroides, which carries an oxidase that serves as a model of the mitochondrial counterpart. The lack of expression of the former variant indicates that the amino acid substitution results in severely altered overall structure of the enzyme. The latter mutation (Gly171Asp in the bacterial oxidase) resulted in a structurally intact enzyme, but with reduced activity (approximately 30%), mainly due to slowed reduction of the redox site heme a. Furthermore, even though the Gly171Asp CytcO pumps protons, an intrinsic proton leak was identified, which would lead to a decreased overall energy-conversion efficiency of the respiratory chain, and would also perturb transport processes such as protein, ion, and metabolite trafficking. Furthermore, the specific leak may act to alter the balance between the electrical and chemical components of the proton electrochemical gradient. cytochrome aa3 ͉ electrochemical ͉ electron transfer ͉ pump ͉ respiratory oxidase

Mitochondrial respiratory defects promote the Warburg effect and cancer progression

“…Mutations in mtDNAcoded subunits of CcO have been reported in prostrate, colon, thyroid, and breast cancers. 1,2 Although some of these mutations have been functionally characterized, 6 the cellular signaling involved and gene targets are largely unknown. Defects in CcO originating from aberrations in nucleus-coded subunits are reported in several pathologic conditions; 7 however, their role in cancer development has not been investigated.…”

Lactic acid in cancer and mitochondrial disease

“…Representative diseases include: neurological disorders, such as mitochondrial dementia [Finsterer, 2009], migraine headaches, Parkinson's disease, Alzheimer's disease, and multiple sclerosis [Keating, 2008]. Others are diabetes [Peterson et al, 2004], steatohepatitis [Serviddio et al, 2008], hypertension [Leonard and Schapira, 2000], sepsis [Lowes et al, 2008], retinopathies [Schaefer, 2008], ischemia-reperfusion injury [Wallace, 1999], and cancer [Namslauer and Brzezinski, 2009;Verma and Kumar, 2007;Czarnecka et al, 2007;Bucay, 2007Bucay, , 2009Barry, 2008].…”

Mitochondrial Genome Instability in Cancer

“…T7275A mutation induced bacterial growth decrease while A6277G transition did not influence bacterial growth but produced a CytcO enzyme with a 30% decrease in its proton-pumping activity accompanied by proton leakage and ROS increase. The introduction of a mt-mutation related to human colon cancer into a bacterium allowed Namslauer and Brzezinski [2009] to mimic the abnormal respiration process observed in malignancies.…”

“…Under culture conditions, both mutant cybrids increased ROS yield and exhibited cell growth properties related to tumorigenesis [Zhou et al, 2007]. Namslauer and Brzezinski [2009], on the other hand, employed a different experimental approach to test the correlation among mt-mutations, OXPHOS disruption, and ROS enhancement. Using site-directed mutagenesis, these researchers introduced into the CytcO gene of Rhodobacter spheroids bacterium 2 non-synonymous mtmutations (A6277G, Gly 1 Asp and T7275C, Ser 1 Pro) previously found in colonic crypts from colon cancer patients [Greaves et al, 2006].…”