Bioenergetics of life, disease and death phenomena

Abstract

In this article, some new aspects of unified cell bioenergetics are presented. From the perspective of unified cell bioenergetics certain subsequent stages of cancer development, from initiation stage, through transformation to metastasis, are analyzed. Here we show that after transformation, cancer cells are permanently exposed to reactive oxygen species, that causes continual random DNA mutations and as a result genome and chromosomal destabilizations. The modern cancer attractor hypothesis has been extended in explaining cancer development. Discussion is conducted in light of current cancerogenesis research, including bioenergetic cancer initiation, the somatic mutation theory and the tissue organization field theory. In the article reasons complicating the discovery of patterns of cancer genome changes and cancer evolution are presented. In addition certain cancer therapeutic aspects are given attention to.

Keywords: Cancer attractors; Cancer development; Cancer transformation; Crabtree effect; Mitochondria; Warburg effect.

Fig. 1

The level of intramitochondrial NADH (mtNADH) in a healthy cell (at t₁), after beginning of disease (at t₂), and after cancer transformation (at t₄). Return to health (trajectory t₂ → t₃) by discharging mitochondria from an excessive amount of high energy molecules (especially mtNADH) is possible up until cancer transformation occurs. After cancer transformation the discharge of mitochondria from an excessive amount of high energy molecules can transpire very slowly (trajectory t₄ → t₅)—see Remarks 2, 5. In this case, cells remain trapped in abnormal attractors

Fig. 2

The positive feedback for ATP (fATP) in a healthy cell, b at disease outset after deep penetration into oxido-fermentative metabolism (due to the reversible Crabtree effect), c after cancer transformation

Fig. 3

Preprogrammed cell transformations. Transformation 1 leads to set 1 of abnormal attractors featuring: sustained proliferative signaling, growth suppressor evasion, resistance to cell death, replicative immortality enablement, deregulated metabolism, and immune destruction evasion. Exemplary (A₁₁ → A_1m) trajectory leads to Transformation 2, and exemplary (A₁₁ → A_1n) trajectory does not lead to transformation. Transformation 2 leads to set 2 of abnormal attractors allowing cancer cells to obtain an additional feature of angiogenesis inducement. Exemplary (A₂₁ → A_2o) trajectory leads to Transformation 3, and exemplary (A₂₁ → A_2p) trajectory does not lead to transformation. Transformation 3 leads to set 3 of abnormal attractors allowing cancer cells to obtain additional invasion and metastasis activation features. Two exemplary trajectories (A₃₁ → A_3r) and (A₃₁ → A_3s) are presented at this level. After attaining abnormal attractors by clones, permanent exposition to ROS causes an accumulation of random DNA mutations resulting in genome instability (GIN) and chromosomal instability (CIN). GIN and CIN cause clones to leave attractors, and by way of auto-transformations to attractors, attain new abnormal attractors (i.e. clones permanently change attractors) or subsequent transformations (see Remarks 3, 4)