LETM1 (leucine zipper–EF hand-containing transmembrane region), a protein with a key role in mitochondrial volume homeostasis through regulation of K⁺/H⁺ exchange (KHE), is involved in respiratory chain biogenesis and in the pathogenesis of seizures in the Wolf–Hirschhorn syndrome (WHS). LETM1 has been recently proposed to catalyze mitochondrial H⁺/Ca²⁺ exchange, which would imply a role in mitochondrial Ca²⁺ homeostasis as well.

LETM1 contains a hydrophobic N-terminal portion spanning the inner membrane and a large hydrophilic portion including the C-terminus located in the matrix. The primary amino acid sequence of the C-terminal part predicts at least two coiled-coil domains and two Ca²⁺-binding EF hand–like motifs. However, the EF hands differ from canonical EF hand motifs by several residues, and the α helices are not directly flanking the Ca²⁺-binding loop. The amino acid sequence of yeast LETM1 proteins lacks these putative Ca²⁺-binding EF hand motifs. The N-terminal region of the LETM1 protein superfamily displays a mitochondrial targeting sequence and a single transmembrane domain. The latter is highly conserved in all orthologues and is rich in proline residues.

In mitochondria, absence of LETM1, causes decompensation of electrophoretic K⁺, resulting in matrix swelling causing, in turn, increased mitophagy and/or cell death¹.