LETM1 is required for mitochondrial homeostasis and cellular viability (Review)

Abstract

Leucine zipper/EF‑hand‑containing transmembrane protein 1 (LETM1) has been identified as the gene responsible for Wolf‑Hirschhorn syndrome (WHS), which is characterized by intellectual disability, epilepsy, growth delay and craniofacial dysgenesis. LETM1 is a mitochondrial inner membrane protein that encodes a homolog of the yeast protein Mdm38, which is involved in mitochondrial morphology. In the present review, the importance of LETM1 in WHS and its role within the mitochondrion was explored. LETM1 governs the mitochondrion ion channel and is involved in mitochondrial respiration. Recent studies have reported that LETM1 acts as a mitochondrial Ca2+/H+ antiporter. LETM1 has also been identified as a K+/H+ exchanger, and serves a role in Mg2+ homeostasis. The function of LETM1 in mitochondria regulation is regulated by its binding partners, carboxyl‑terminal modulator protein and mitochondrial ribosomal protein L36. Therefore, we describe the remarkable role of LETM1 in mitochondrial network physiology and its function in mitochondrion‑mediated cell death. In the context of these findings, we suggest that the participation of LETM1 in tumorigenesis through the alteration of cancer metabolism should be investigated. This review provides a comprehensive description of LETM1 function, which is required for mitochondrial homeostasis and cellular viability.

Figure 1.

LETM1 structure and localization. (A) Schematic representation of LETM1 and LETM2. Specific domains and sites are symbolized by respective colors as indicated. (B) Sub-mitochondrial localization of LETM1. OM, Outer Membrane; IM, inner membrane; LETM1, leucine zipper/EF-hand-containing transmembrane protein 1.

Figure 1.

LETM1 structure and localization. (A) Schematic representation of LETM1 and LETM2. Specific domains and sites are symbolized by respective colors as indicated. (B) Sub-mitochondrial localization of LETM1. OM, Outer Membrane; IM, inner membrane; LETM1, leucine zipper/EF-hand-containing transmembrane protein 1.

Figure 2.

Regulation of ion-channels in mitochondria by LETM1. MCU drives massive calcium entry with high cytosolic Ca²⁺ concentrations (>10 µM) in microdomains near Ca⁺² release channels on ER but LETM1 functions as Ca²⁺/H⁺ antiporter, at low cytosolic Ca²⁺ concentrations (>100 nM). The pH gradient generated by the ETC limits its action. It can also extrude Ca²⁺ along with the NCLX during Ca²⁺ overload. Furthermore, it also functions as the K⁺/H⁺ exchanger as well as a Mg²⁺ transporter. ETC, electron transport chain; MCU, Mitochondrial Ca²⁺ uniporter; NCLX, Na⁺-Ca⁺ exchanger; VDAC, voltage dependent anion channel; SR, sarcoplasmic Reticulum; ER, endoplasmic reticulum; LETM1, leucine zipper/EF-hand-containing transmembrane protein 1.

Figure 3.

Schematic representation of proposed LETM1 function. Schematic diagram depicting the proposed physiological as well as pathophysiological roles of LETM1. It shows the functions of LETM1 in the mitochondria and the consequences of loss in these functions. LETM1, leucine zipper/EF-hand-containing transmembrane protein 1.