Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

Abstract

Previously, renal cell carcinoma tissues were reported to display a marked reduction of components of the respiratory chain. To elucidate a possible relationship between tumourigenesis and alterations of oxidative phosphorylation, we screened for mutations of the mitochondrial DNA (mtDNA) in renal carcinoma tissues and patient-matched normal kidney cortex. Seven of the 15 samples investigated revealed at least one somatic heteroplasmic mutation as determined by denaturating HPLC analysis (DHPLC). No homoplasmic somatic mutations were observed. Actually, half of the mutations presented a level of heteroplasmy below 25%, which could be easily overlooked by automated sequence analysis. The somatic mutations included four known D-loop mutations, four so far unreported mutations in ribosomal genes, one synonymous change in the ND4 gene and four nonsynonymous base changes in the ND2, COI, ND5 and ND4L genes. One renal cell carcinoma tissue showed a somatic A3243G mutation, which is a known frequent cause of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episode) and specific compensatory alterations of enzyme activities of the respiratory chain in the tumour tissue. No difference between histopathology and clinical progression compared to the other tumour tissues was observed. In conclusion, the low abundance as well as the frequently observed low level of heteroplasmy of somatic mtDNA mutations indicates that the decreased aerobic energy capacity in tumour tissue seems to be mediated by a general nuclear regulated mechanism.

Mitochondria and cancer

“…These include renal adenocarcinoma, colon cancer cells, head and neck tumours, astrocytic tumours, thyroid tumours, breast tumours, ovarian tumours, prostate and bladder cancer, neuroblastomas and oncocytomas 19–24 . Although technical and interpretive errors were common in early publications on mtDNA mutations in cancer 25–27 , the identification of clearly deleterious mtDNA mutations in cancer tissues — such as an intragenic deletion 8 or the common tRNA Leu(UUR) A3243G MELAS mutation 26 — validate the relevance of pathogenic mutations in neoplastic transformation. The importance of the mtDNA in cancer has been confirmed by the exchange of cancer cell mtDNA with pathogenic or normal mtDNA, resulting in alterations of cancer cell phenotypes 28–31 .…”

93 Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma

“…The A3243G mutation might be sporadically associated with other tumor types because it was also detected in a colon cancer sample (28) and a renal cell carcinoma (24).…”

“…Determination of mutational load of the A3243G mutation. The percentage of mutational load was quantified by densitometry of ethidium bromide -stained agarose gels, as described previously (24).…”

A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

“…The identification of clearly deleterious mtDNA mutations in cancer tissues - such as an intragenic deletion [21] or the common tRNALeu (UUR) A3243G MELAS mutation, or, even more so, very rare clearly pathogenic mutations in complex I [22] (for a review see [19, 23]) - underline the relevance of pathogenic mtDNA mutations in neoplastic transformation. In recent years a high number of point mutations, either germline or somatic, insertions and deletions in mtDNA have been identified in multiple cancers [24–28].…”