Abstract:
Cells function through three interconnected systems: energy flow, metabolism and genetic information. Recent work suggests that these systems arose in that order from the origin of life itself: a geochemical protonmotive force across cell-like inorganic pores in alkaline hydrothermal systems drove CO2 fixation into spontaneous protometabolism with a similar topology to the deeply conserved core of metabolism, which gave rise to genes through direct physical interactions.
The core of metabolism is the Krebs cycle, which in bacteria may be driven in reverse by membrane potential to fix CO2, generating the precursors for cell growth. Even in modern eukaryotic cells the Krebs cycle rarely functions simply as an oxidative cycle. In cancer and viral infections such as Covid, Krebs cycle flux can be driven partly in reverse by membrane potential to form useful biosynthetic precursors, which in turn upregulate the mTOR axis and downregulate sirtuins and autophagy. This rewiring may also happen with age, shaping epigenetic state and mimicking a pseudo-programme for ageing.
Work in isogenic fly lines with mismatched mitochondrial DNA shows that complex I function impacts not only on oxidative phosphorylation but also Krebs cycle flux, intermediary metabolism, gene expression and phenotypic outcomes including fitness and longevity. Suppression of complex I expression can maintain ROS flux within homeostatic limits, even at the cost of viability. Such drastic changes could be offset by mitochondrial dynamics, notably changes in cristae structure. More open cristae will lower membrane potential and ROS flux, making it easier for complex I to pump and restoring redox state, but at what cost beyond lower ATP synthesis? Work on the mechanism of volatile general anaesthetics in flies suggests that complex I can act as a supramolecular engine, in which synchronized electron flow and proton flux through parallel cristae can generate oscillating magnetic fields with sufficient strength to signal to the plasma membrane. Disruptions in cristae structure with ageing are likely to affect the dynamics of such mitochondrial integration within cell and tissue networks.