The awakening of an advanced malignant cancer: an insult to the mitochondrial genome

Abstract

Background: In only months-to-years a primary cancer can progress to an advanced phenotype that is metastatic and resistant to clinical treatments. As early as the 1900s, it was discovered that the progression of a cancer to the advanced phenotype is often associated with a shift in the metabolic profile of the disease from a state of respiration to anaerobic fermentation - a phenomenon denoted as the Warburg Effect.

Scope of review: Reports in the literature strongly suggest that the Warburg Effect is generated as a response to a loss in the integrity of the sequence and/or copy number of the mitochondrial genome content within a cancer.

Major conclusions: Multiple studies regarding the progression of cancer indicate that mutation, and/or, a flux in the copy number, of the mitochondrial genome content can support the early development of a cancer, until; the mutational load and/or the reduction-to-depletion of the copy number of the mitochondrial genome content induces the progression of the disease to an advanced phenotype.

General significance: Collectively, evidence has revealed that the human cell has incorporated the mitochondrial genome content into a cellular mechanism that, when pathologically actuated, can de(un)differentiate a cancer from the parental tissue of origin into an autonomous disease that disrupts the hierarchical structure-and-function of the human body. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.

Figure 1. The Mitochondrial Genome Content in Cancer Development

In general, cells of human origin are respiratory-competent with mitochondria that harbor a mixture (haplotype) of sequences of the mitochondrial genome. Evidence indicates that in carcinogenesis the copy number of the mitochondrial genome is amplified, potentially as a consequence to the generation, and/or heteroplasmic-to-homoplasmic shift, of a mutant sequence of the mitochondrial genome; until, the progression of the cancer to an advanced (fermentative) phenotype is observed with a reduction-to-depletion of the mitochondrial genome content.

Figure 2. Mitochondrial Genome Knock-In (ρ0) and Mitochondrial Genome Knock-Out (Cybrid) Models

In general, cells of human origin are respiratory-competent with mitochondria that harbor the mitochondrial genome. Viable cells (ρ0) can be generated with the depletion of the mitochondrial genome. As a control, the mitochondrial genome content can be reconstituted to ρ0 cells with the fusion of ρ0 to cytoplast that act as membrane bound donors of mitochondria, and, thus, the mitochondrial genome.