A direct, MFRN-independent Fe(II) transfer pathway at mitochondria-lysosome contacts

Mitochondrial iron homeostasis plays a crucial role in respiration and redox balance, with dysregulation linked to neurodegeneration, cardiomyopathy, and metabolic diseases. Traditionally, it was believed that mitochondria obtain Fe(II) directly from the cytosolic labile iron pool (LIP) through MFRN transporters. However, researchers have now discovered an alternative pathway that bypasses the LIP at mitochondria-lysosome contacts (MLCs), challenging the previous understanding.

By employing live-cell structured illumination microscopy (SIM), scientists have directly observed Fe(II) transfer occurring at MLCs. This finding reveals that the proteins VPS39, TOMM22, and SFXN1 play essential roles in this process. VPS39 and TOMM22 help stabilize the MLCs, while SFXN1 acts as the core effector protein responsible for the MLC-dependent Fe(II) transport.

Interestingly, researchers found that knocking down SFXN1 significantly lowers mitochondrial Fe(II) levels, even though SFXN1 is primarily known for its role in serine transport. This observation highlights the importance of SFXN1 in maintaining mitochondrial Fe(II) levels.

The identification of this direct, MFRN-independent Fe(II) transfer pathway at MLCs represents a significant finding in understanding mitochondrial iron acquisition. This newly discovered route supports redox homeostasis and may provide valuable insights into the development of therapies for diseases associated with mitochondrial iron dysregulation.