Metabolism and cell fate

Jennings (1906) argued that the metabolic state of an organism seems the most important factor determining its behaviour.¹ In his account, internal metabolic states can drive long trains of activity without any outside stimulus, and they also shape how the animal responds to stimuli when they come. Loeb (1912) came at the same problem from the egg. He found that the fertilized sea-urchin egg develops only in free oxygen, and he concluded that the sperm starts development by accelerating oxidations in the egg.² He reported that Warburg and others measured the rise in oxidation speed at fertilization as four to six times the starting value.²

Bayliss (1915) reported that Warburg and Meyerhof found yeast activity greatly diminished by rubbing the cells with sand.³ This pointed to oxidation as dependent on cell structure, not only on dissolved chemistry. Hill (1926) summarized Warburg's group as finding that many biological oxidations probably occur as surface phenomena, catalysed by iron atoms embedded in the surface.⁴ Lillie (1923) reported that narcotics lowered oxygen consumption in vertebrate tissue, but only at concentrations much higher than normal narcosis needs. He read this as against Verworn and others, who had linked anaesthesia to reduced oxidation.⁵

Ferramosca and Zara (2014) describe a debate in sperm biology that has run for decades. Researchers disagree on whether the extra energy for capacitation comes from glycolysis or from mitochondrial oxidative phosphorylation. The authors conclude that the main source may differ between mammalian species, and in humans may depend on the substrates and oxygen available.⁶ Pai and colleagues (2020) add a link to bioelectric signalling. They note that HCN channels have a threshold voltage affected by metabolic state, and that the roles of these channels in embryonic development are largely unexplored.⁷

Schofield and colleagues (2020) note that cancer cells, known for overflow metabolism, have altered membrane potential. They report that engineered redox reactions that change the NADH/NAD+ ratio shift the initiation point of the Warburg effect in bacteria and yeast.⁸ They call the bioelectrical explanation testable but not yet validated.⁸ Rottenberg (2023) reviews a Drosophila study in which old intestinal stem cells showed a Warburg-like shift. He accepts that the shift may go with lower mitochondrial membrane potential, but doubts the measurement, because the data are average cell fluorescence and the probe may not be evenly spread among mitochondria.⁹