An Apoptotic and Endosymbiotic Explanation of the Warburg and the Inverse Warburg Hypotheses

Abstract

Otto Warburg, a Nobel prize winner, observed that cancer cells typically "switch" from aerobic to anaerobic respiration. He hypothesized that mitochondrial damage induces neoplastic transformation. In contrast, pathological aging is observed mainly in neuron cells in neurodegenerative diseases. Oxidative respiration is particularly active in neurons. There is inverse comorbidity between cancer and neurodegenerative diseases. This led to the creation of the "inverse Warburg hypothesis", according to which excessive mitochondrial activity induces pathological aging. The findings of our studies suggest that both the Warburg effect and the "inverse Warburg hypothesis" can be elucidated by the activation or suppression of apoptosis through oxidative respiration. The key outcome of our phylogenetic studies was the discovery that apoptosis and apoptosis-like cell death evolved due to an evolutionary "arms race" conducted between "prey" protomitochondrion and "predator" primitive eukaryotes. The ancestral protomitochondrial machinery produces and releases toxic mitochondrial proteins. Extant apoptotic factors evolved from these toxins. Our experiments indicate that the mitochondrial machinery is directly involved in adaptation to aerobic conditions. Additionally, our hypothesis is supported by the fact that different apoptotic factors are directly involved in respiration.

Keywords: Alzheimer; Warburg effect; apoptosis; inverse Warburg effect; yeast.

Figure 1

The Warburg and inverse Warburg effects in the ancestral state. There was an antagonistic relationship between prey (protomitochondrion, camel ovoids) and predators (protoeurkaryotes, black and doted lines). They killed each another. There was a dynamic equilibrium. Aerobic conditions caused shift of balance towards protomitochondrions and protoeukaryotes were killed (inverse Warburg effect). In contrast, under anaerobic conditions, the struggle was won by protoeukarytes. Other graphical elements: pink ovals—nucleus or fragmented nucleus, greenish circles—vesicles.