Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent “Golgicrine” Activities

Abstract

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor. This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca 2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca 2+-homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca 2+-homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol-and Ca 2+-homeostasis-dependent Golgicrine issue.

Two Undervalued Functions of the Golgi Apparatus: Removal of Excess Ca2+ and Biosynthesis of Farnesol-Like Sesquiterpenoids, Possibly as Ca2+-Pump Agonists and Membrane “Fluidizers–Plasticizers”

“…It is a central meeting point for the endocytotic and exocytotic systems in eukaryotic cells ( Barlow et al, 2018 ). Last but not least, through logical deduction, De Loof and Schoofs (2019b , d) came to the conclusion that the Golgi system is the most probable site of synthesis of endogenousFLSs) (section “The Golgi Apparatus as a Probable Subcellular Site of Synthesis of Farnesol/Farnesol-Like Sesquiterpenoid: Origin of This Idea”).…”

“…Ablation of the CA not only affects the Golgi systems but nearly all aspects of cell physiology, including lipid, protein, and ecdysteroid biosynthesis, the multiplication of mitochondria, etc. It visualized in a few images that farnesol esters are indeed the master hormone(s) in insect physiology and development ( De Loof and Schoofs, 2019b , d ). Both reimplantation of active CA and administration of synthetic JH (dissolved in an oil to act as a slow-release formula) temporarily (= within a few days) rescued the observed phenotype and thus demonstrated that absence of farnesol/JH is the real cause of the cell physiological effects induced by allatectomy ( De Loof and Lagasse, 1970 ).…”

“…The major objection is that, up to the present day, it has not been experimentally demonstrated that farnesol/JHs, which are highly hydrophobic molecules, ever enter the nucleus with its internal hydrophilic watery environment. As long as the in situ binding between JH and its Met-transcription factor inside the nucleus has not been experimentally proven, Met does not meet the required conditions to be classified as a “genuine receptor.” According to De Loof and Schoofs (2019a , d , e ), there is no problem to classify MET as a JH target . Even more, it is probable that Met is a Ca 2+ -sensitive target ( De Loof and Schoofs, 2019e , and this paper).…”

“…The successive steps in this development have recently been reviewed by De Loof and Schoofs (2019d , e) . In short, up to 1995, the CA were assumed to be the sole site of synthesis of JHs.…”

“…They named it “exocrine JH synthesis.” They also reported that this male accessory gland (MAG) JH was not secreted into the hemolymph, but instead left the male body along with secretory proteins that during copulation are transferred into the female’s genital system. This selectivity, or better unidirectionality, in JH secretion triggered De Loof and Schoofs (2019d) to search for an explanation for this at first sight unusual transport of a hydrophobic/lipophilic hormone. When upon analyzing Schmialek’s (1961) experimental data, the idea emerged that the most plausible and logical answer to the question how farnesol can end up in the lumen of the alimentary canal of larval mealworms, was that this requires a key contribution of Golgi systems of the gut’s epithelial cells.…”