MFSD7C: A Solute Carrier Linking Heme and Calcium in Mitochondrial Energy Metabolism

Abstract

Major Facilitator Superfamily Domain-Containing 7C (MFSD7C) is an orphan solute carrier. In humans, loss-of-function mutations in MFSD7C cause Fowler syndrome, an often prenatally lethal disorder that affects brain development and angiogenesis. MFSD7C and its closely related paralog MFSD7B, have been proposed to function as heme transporters, however this hypothesis was challenged by several groups. We now show that MFSD7C localizes to mitochondria where it interacts with the electron transport chain complex. Loss of MFSD7C in various cell lines and primary cells results in increased mitochondrial respiration, but decreased ATP synthesis. Using several different methods, we show that the loss of MFSD7C stimulates cellular thermogenesis. The soluble N-terminal domain of MFSD7C contains conserved heme-binding motifs and directly binds two molecules of heme. We show that heme treatment of cells phenocopies the loss of MFSD7C, and that the N-terminal domain is essential for this effect. In order to find the transport substrate for MFSD7C, we purified the protein and performed a candidate substrate screen using thermostability-shift assay. The screen revealed that calcium is a candidate substrate for MFSD7C. Transport assays with isolated mitochondria suggest that MFSD7C may function as a mitochondrial calcium transporter. In conclusion, our experiments suggest that MFSD7C is a mitochondrial calcium transporter that switches ATP synthesis to thermogenesis in response to heme.