LETM1 has a prominent function in mitochondrial K+ and Ca2+ homeostasis as the long-sought H+/cation exchanger.
Under physiological conditions LETM1 provides mitochondria with a pathway for cation release.
LETM1 is essential for the survival of all organisms tested so far, which highlights the importance of mitochondrial cation homeostasis for cell function.
The recently resolved hexameric structure suggests that LETM1 could mediate cation exchange without the need for additional proteins.
Mitochondrial function is essential for life. Therefore, it is unsurprising that perturbations in mitochondrial function have wide-ranging consequences in the cell. High-throughput screening has identified essential genes required for cellular survival and fitness. One such gene is LETM1. The undisputed function of LETM1 from yeast to human is to maintain the mitochondrial osmotic balance. Osmotic imbalance has been demonstrated to affect mitochondrial morphology, dynamics, and, more recently, metabolism. Whether conservation of osmotic homeostasis by LETM1 occurs by extrusion of excess mitochondrial potassium (K+), calcium (Ca2+), or both has been a matter of dispute over the past 10 years. In this Opinion, we report and discuss recent findings on LETM1 structure, essentiality, and function and its involvement in Wolf–Hirschhorn syndrome (WHS) and seizures.
