The leucine zipper-EF band transmembrane protein 1, LetM1.  Reduces mitochondrial Ca²⁺ uptake in response to cytoplasmic Ca²⁺entry in pancreatic beta cells (Alam et al. 2012).  LetM1 is a cation/Ca²⁺ transporter, with apparent affinities of cations in the order Ca²⁺ = Mn²⁺ > Gd³⁺ = La³⁺ > Sr²⁺ >> Ba²⁺, Mg²⁺, K⁺, Na⁺ (Shao et al. 2016). The LetM1 turnover rate is only 2 Ca²⁺/sec with a K_m of ~ 25 microM. LetM1 mediates electroneutral 1 Ca²⁺/2 H⁺ antiport (Tsai et al. 2013).  However, NCLX (2.A.19.4.4), rather than LetM1, may mediate miltochondrial Ca²⁺ extrusion (De Marchi et al. 2014).  Letm1 is associated with seizure attacks in Wolf-Hirschhorn syndrome, and its inhibition and mitochondrial dysfunctions contribute to the development of epileptic seizures. An appropriate LetM1 level may be critical for maintaining normal neuronal functions (Zhang et al. 2014).  Glu221 in the mouse orthologue is essential. The protein is a hexamer with a central cavity and exhibits two different conformational states (Shao et al. 2016). Abnormal levels occur in plasma neuron-derived extracellular vesicles in early schizophrenia and other neurodevelopmental diseases (Goetzl et al. 2022).  LetM1 has an osmoregulatory function controlling mitochondrial volume and ion homeostasis (Kaiyrzhanov et al. 2022).  Bi-allelic LETM1 variants are associated with defective mitochondrial K⁺ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies (Kaiyrzhanov et al. 2022).