pH plays a critical role in maintaining normal cellular activities. It helps maintain the structure and function of various proteins, dictates the charge on cellular membranes, and is crucial for metabolic reactions inside the cell. Moreover, cells use the energy from the proton motive force to generate ATP.

Cytosolic pH

Under physiological conditions, the cytosolic pH is slightly more acidic than the extracellular pH. However, cells must prevent further acidification of their cytosol to maintain their membrane potential and carry out normal functioning. Therefore, they employ several specialized proton-translocating machinery—antiporters, symporters, and proton-pumping ATPases—to tightly regulate the steady-state pH.

Cellular Organelles and pH Homeostasis

The compartmentalization inside the eukaryotic cells helps to provide distinct environmental conditions to carry out specific functions within different membrane-enclosed organelles. The internal pH in these different compartments is highly variable, but it is an important determinant of their effective functioning.

For example, cytochromes located on the inner mitochondrial membrane efflux protons using energy from electron flow. This helps to establish a proton gradient across the mitochondrial membrane that is used to generate chemical energy in the form of ATP. Similarly, lysosomes maintain an internal acidic pH by pumping protons from the cytosol using energy from ATP hydrolysis. This is essential for the functioning of the lysosomal enzymes.

However, some organelles, including the nucleus, endoplasmic reticulum, and peroxisomes, need to maintain their internal pH in equilibrium with the cytoplasm. Therefore, they lack intrinsic pH-regulatory systems and are highly permeable to protons.

Dysregulation of Intracellular pH

Certain metabolic or genetic conditions may disrupt the steady-state pH of the cytoplasm or the organelles inside the cell and lead to disease. For example, mutations in chloride carriers, such as CLCN6 and CLCN7, present on late endosomes and lysosomes have been linked to osteoporosis and lysosomal storage disease. Similarly, mutations in the CLCN5 channel hinder luminal acidification and production of early endosomes in renal epithelial cells and can eventually lead to kidney failure.