The osteoblast sodium-citrate co-transporter (SLC13A5): A gatekeeper between global citrate homeostasis and tissue mineralization

Abstract

It has been known for decades that bone stores high concentrations of citrate, a pivotal TCA cycle intermediate, but surprisingly little attention has been paid to explaining this curious phenomenon. Recent studies linking mutations in the sodium-citrate co-transporter (SLC13A5) to a rare neonatal epilepsy have sparked renewed interest in the study of the mechanisms controlling citrate homeostasis and mineral citrate deposition as all affected children display tooth hypomineralization. Studies from our lab using metabolic flux analysis indicate that SLC13A5 is at the center of a specialized metabolic pathway in bone, which finetunes the uptake of extracellular citrate and endogenous production in the mitochondria enabling the osteoblast to deposit citrate during cycles of bone mineralization. Loss of function of this pathway impacts circulating citrate levels and compromises bone mineral structure. These findings implicate SLC13A5 as a gatekeeper for global citrate homeostasis and is required for normal biomechanical physiological functions of bone.