Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Abstract

Exocytic and endocytic compartments each have their own unique luminal ion and pH environment that is important for their normal functioning. A failure to maintain this environment - the loss of homeostasis - is not uncommon. In the worst case, all the main Golgi functions, including glycosylation, membrane trafficking and protein sorting, can be perturbed. Several factors contribute to Golgi homeostasis. These include not only ions such as H⁺, Ca²⁺, Mg²⁺, Mn²⁺, but also Golgi redox state and nitric oxide (NO) levels, both of which are dependent on the oxygen levels in the cells. Changes to any one of these factors have consequences on Golgi functions, the nature of which can be dissimilar or similar depending upon the defects themselves. For example, altered Golgi pH homeostasis gives rise to Cutis laxa disease, in which glycosylation and membrane trafficking are both affected, while altered Ca²⁺ homeostasis due to the mutated SCPA1 gene in Hailey-Hailey disease, perturbs various protein sorting, proteolytic cleavage and membrane trafficking events in the Golgi. This review gives an overview of the molecular machineries involved in the maintenance of Golgi ion, pH and redox homeostasis, followed by a discussion of the organelle dysfunction and disease that frequently result from their breakdown. Congenital disorders of glycosylation (CDGs) are discussed only when they contribute directly to Golgi pH, ion or redox homeostasis. Current evidence emphasizes that, rather than being mere supporting factors, Golgi pH, ion and redox homeostasis are in fact key players that orchestrate and maintain all Golgi functions.

Keywords: Golgi pH; Golgi redox state; cancer; glycosylation; homeostasis; protein sorting.

Figure 1

The figure shows short term (min) changes in the Golgi luminal pH after treating intact cells with the pH gradient dissipating agents (red and blue dots) and the V-ATPase inhibitor Concanamycin A (green dots). Note the differential pH responses to these drugs, and the rate of H⁺ leakage across the Golgi membranes after shutting down the V-ATPase by the inhibitor used.

Figure 2

A simplified summary of the Golgi-localized ion pumps, transporters and channels identified at the protein level, or based upon Golgi physiological measurements. The question marks depict those for which direct proof for the presence of the protein in question needs to be verified. The arrows depict their putative direction of functioning in ion transport. The elusive H+ leak channel is also marked by question mark to depict the lack of knowledge about its identity. For additional details, see the text.