Abstract
Although the observation of aerobic glycolysis of tumor cells by Otto v. Warburg had demonstrated abnormalities of mitochondrial energy metabolism in cancer decades ago, there was no clear evidence for a functional role of mutant mitochondrial proteins in cancer development until the early years of the 21st century. In the year 2000, a major breakthrough was achieved by the observation, that several genes coding for subunits of the respiratory chain (ETC) complex II, succinate dehydrogenase (SDH) are tumor suppressor genes in heritable paragangliomas, fulfilling Knudson’s classical two-hit hypothesis. A functional inactivation of both alleles by germline mutations and chromosomal losses in the tumor tissue was found in the patients. Later, SDH mutations were also identified in sporadic paragangliomas and pheochromocytomas. Genes of the mitochondrial ATP-synthase and of mitochondrial iron homeostasis have been implicated in cancer development at the level of cell culture and mouse experiments. In contrast to the well established role of some nuclear SDH genes, a functional impact of the mitochondrial genome itself (mtDNA) in cancer development remains unclear. Nevertheless, the extremely high frequency of mtDNA mutations in solid tumors raises the question, whether this small circular genome might be applicable to early cancer detection. This is a meaningful approach, especially in cancers, which tend to spread tumor cells early into bodily fluids or faeces, which can be screened by non-invasive methods.
Highlights
The high abundance and high activity of the HK II hexokinase isoform in the tumor cells may be an important trigger of enhanced glucose utilization and lactate production of tumor cells even under normoxic conditions, under which mitochondrial ATP is available as an additional fuel of the hexokinase reaction
Heterozygeous missense, nonsense- or frameshift-mutations in the POLG gene do usually not cause a depletion of mtDNA, but lead to a fragility of the mitochondrial genome, which is prone to multiple large scale deletions in a proportion of mtDNA molecules, which can be detected in Southern blots of skeletal muscle DNA
Some mtDNA mutations may enhance tumor growth, the enrichment of mutated mtDNA in solid human tumors can be explained by random drift, without need of any selective advantage
Summary
More than eighty years ago, Otto Heinrich Warburg began his pioneering work on tumor cell metabolism, which culminated in the hypothesis that endogenous respiration defects of cancer cells, accompanied by the slow development of an enhanced ‘aerobic glycolysis’ during carcinogenesis,` would be a metabolic switch, defining the root of cancer [1,2]. The high abundance and high activity (decreased product inhibition) of the HK II hexokinase isoform in the tumor cells may be an important trigger of enhanced glucose utilization and lactate production of tumor cells even under normoxic conditions, under which mitochondrial ATP is available as an additional fuel of the hexokinase reaction. Besides these metabolic considerations, another role of HK II in creating a more malignant phenotype may be discussed, since VDAC is an essential component of the mitochondrial permeability transition pore (mPTP). This could be demonstrated by some authors [22, 23], while disruption of the HKIIVDAC-interaction enhanced apoptosis induction [24]
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