The SLC41 Family of Magnesium Transporters: Molecular Regulators of Magnesium Homeostasis and Their Multifaceted Roles in Human Diseases

Magnesium ion (Mg²⁺), particularly its free intracellular form, is indispensable for regulating diverse cellular functions. This critical role implies the existence of dedicated transporters and channels in the plasma membrane that coordinate Mg²⁺ uptake, intracellular storage, and efflux to maintain homeostasis. Although numerous molecular entities responsible for such Mg²⁺ transport have been reported over the past decades, there is still limited knowledge of their precise functions and disease implications. This review focuses on the solute carrier family 41 (SLC41), which consists of three isoforms (A1, A2, and A3) that share homology with the prokaryotic magnesium transporter E (MgtE) Mg²⁺ transporter family. Accumulating evidence has established SLC41A1 as the Na⁺/Mg²⁺ exchanger-a predominant Mg²⁺-efflux system. By contrast, the subcellular site of SLC41A2-mediated Mg²⁺ flux remains undefined, with potential roles at either the plasma membrane or organellar membranes, and SLC41A3 facilitates Na⁺-dependent Mg²⁺ efflux from mitochondria. Additionally, several studies have reported the association between SLC41s and diseases, including Parkinson's disease, hepatocellular carcinoma, and nephronophthisis-related ciliopathies. By synthesizing current knowledge, this review aims to enhance the understanding of SLC41 transporters in health and disease and to explore their potential as therapeutic targets for clinical intervention.