The grand-scale biology of PGRMC1: How eukaryogenesis and the ediacaran fauna illuminate S2R-associated pathologies like cancer and dementia

The PGRMC1 gene may have originated in a bacterium that contributed to the eukaryogenic endosymbiosis between an Asgard archaeon host cell and endosymbiotic proto-mitochondrion, when molecular oxygen (O2) levels were first rising and the proto-mitochondrion detoxified O2 for the anaerobic Asgard host. The ancestral PGRMC1 gene was involved in sterol production, hypothetically to modulate proto-mitochondrial activity in response to O2: a function conserved from yeast to humans. The early eukaryotic gene hypothetically gained a membrane trafficking motif (MTM) to transfer sterols to mitochondria. Modern PGRMC1 retains sterol metabolism and membrane-trafficking functions, and both sigma-1 and sigma-2 receptor (S2R) have been associated with sterol transport. Formatively in animal evolution, with the common ancestor of Bilateria and Cnidaria (CABAC) that predated the Ediacaran era, PGRMC1 gained two tyrosines, with one in the putative MTM. The CABAC was the first organism with a gastrulation organiser, which initiates the process of epigenetic embryological tissue differentiation that was later expanded in CABAC ancestors to develop the diversity of complex body plans evidenced by the Ediacaran fauna and the Cambrian explosion. Maintenance of correct cell differentiation status is critical for human health. Mutating PGRMC1 phosphorylation sites causes changes in metabolism, genomic CpG methylation, mitochondrial form and function, and reduced cancer growth, with pathways analysis indicating processes associated with body pattern establishment and differentiation. PGRMC1 membrane trafficking is required for the mechanism of action of synaptorestorative anti-Alzheimer's disease (AD) S2R candidate drug CT118. AD is characterised by epigenetic and mitochondrial variability, and the three most heavily studied markers are ApoE3, Amyloid beta, and Tau. An overarching hypothesis is presented relating all these AD traits to PGRMC1 biology, consistent with a centrally causative but hitherto neglected role for PGRMC1 involvement with the aetiology of AD.