Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism.

Signal transduction is the process by which external or internal signals exert their intracellular biological effects and by which intracellular communication is regulated. An important component of the signalling pathway is the second messenger, which is produced upon stimulation of the cell and mediates its effects downstream through phosphorylation and dephosphorylation of target proteins. Intracellular accumulation or deficiency of metabolites that serve as second messengers, due to inborn errors of their metabolism, may lead to perturbation of signalling pathways and disruption of the balance between them, serving as a missing link between the genotype, biochemical phenotype and clinical phenotype. The main second messengers that are putatively associated with the pathogenesis of IEM are 'bioactive lipids' (complex lipids and long-chain fatty acids), 'calcium', 'stress' (osmotic, reactive oxygen/nitorgen species, misfolded proteins and others) and 'metabolic' (AMP/ATP ratio, leucine, glutamine). They act through protein kinase C, calcium dependent kinases (CamK) and phosphatase (CN), 'stress-mediated' kinases (MAPK) and AMP/ATP-dependent kinase (AMPK). These signalling pathways lead to cell proliferation, inflammatory response, autophagy (and mitophagy) and apoptosis, suggesting that there are only few final common pathways involved in this pathogenetic mechanism. Questions remain regarding the complexity of the effects of the accumulating metabolites on different signalling pathways, and regarding the relative role and origin of 'proxy' second messengers such as reactive oxygen species. A better understanding of the signalling pathways in IEM may enhance the development of novel therapies in situations where normalising intracellular concentrations of the second messenger is impossible or impractical.