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2015 ; 21
(ä): 3736-9
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Cancer: Mitochondrial Origins
#MMPMID26621573
Stefano GB
; Kream RM
Med Sci Monit
2015[Dec]; 21
(ä): 3736-9
PMID26621573
show ga
The primacy of glucose derived from photosynthesis as an existential source of
chemical energy across plant and animal phyla is universally accepted as a core
principle in the biological sciences. In mammalian cells, initial processing of
glucose to triose phosphate intermediates takes place within the cytosolic
glycolytic pathway and terminates with temporal transport of reducing equivalents
derived from pyruvate metabolism by membrane-associated respiratory complexes in
the mitochondrial matrix. The intra-mitochondrial availability of molecular
oxygen as the ultimate electron acceptor drives the evolutionary fashioned
chemiosmotic production of ATP as a high-efficiency biological process. The
mechanistic bases of carcinogenesis have demonstrated profound alteration of
normative mitochondrial function, notably dysregulated respiratory processes.
Accordingly, the classic Warburg effect functionally links aerobic glycolysis,
aberrant production and release of lactate, and metabolic down-regulation of
mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise,
however, that aerobic fermentation by cancer cells may also represent a
developmental re-emergence of an evolutionarily conserved early phenotype, which
was "sidelined" with the emergence of mitochondrial oxidative phosphorylation as
a primary mechanism for ATP production in normal cells. Regardless of
state-dependent physiological status in mixed populations of cancer cells, it has
been established that mitochondria are functionally linked to the initiation of
cancer and its progression. Biochemical, molecular, and physiological differences
in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific
expression of selected nuclear genes, may represent major focal points for novel
targeting and elimination of cancer cells in metastatic disease afflicting human
populations. To date, and despite considerable research efforts, the practical
realization of advanced mitochondrial targeted therapies has not been
forthcoming.
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