Conditional knockdown of hMRS2 results in loss of mitochondrial Mg + uptake and cell death

Abstract The human gene MRS2L encodes a mitochondrial protein distantly related to CorA Mg 2+ transport proteins. Constitutive shRNA‐mediated knockdown of hMRS2 in human HEK‐293 cell line was found here to cause death. To further study its role in Mg 2+ transport, we have established stable cell lines with conditionally expressing shRNAs directed against hMRS2L . The cells expressing shRNA for several generations exhibited lower steady‐state levels of free mitochondrial Mg 2+ ([Mg 2+ ] m ) and reduced capacity of mitochondrial Mg 2+ uptake than control cells. Long‐term expression of shRNAs resulted in loss of mitochondrial respiratory complex I, decreased mitochondrial membrane potential and cell death. We conclude that hMrs2 is the major transport protein for Mg + uptake into mitochondria and that expression of hMrs2 is essential for the maintenance of respiratory complex I and cell viability.