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 Ca 2+ /H + antiporter. LETM1 has also been identified as a K + /H + exchanger, and serves a role in Mg 2+ 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.

Population Structure, and Selection Signatures Underlying High-Altitude Adaptation Inferred From Genome-Wide Copy Number Variations in Chinese Indigenous Cattle

“…Over 90% of mammalian O 2 is consumed through mitochondrial respiration (Rolfe and Brown, 1997). LETM1 encodes the Leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) embedded in the mitochondrial inner membrane, and it plays an essential role in maintaining normal mitochondrial morphology and cell viability (Schlickum et al, 2004;Li et al, 2019). Nevertheless, LETM1 overexpression can lead to decreases in mitochondrial ATP production and O 2 consumption, mitochondrial dysmorphology, swollen mitochondria cristae, and an increase in fragmentation in Hela cells (Piao et al, 2009a;Piao et al, 2009b).…”

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

“…For example, ACBD7, ACOT11, and ACSL6 have been shown to bind and convert long chain fatty acids to acyl-CoA for degradation by FAO ( 61–64 ). LPIN3 has a general role in regulating fatty acid metabolism ( 65 ) and LETM1 is thought to regulate mitochondrial dynamics and maintain normal mitochondrial morphology ( 66 ). Other genes upregulated in the oleic acid module included SYAP1 and zinc finger protein, ZFP30 , that have roles in adipogenesis ( 67, 68 ).…”

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

“…It is now believed that the transport of Ca 2+ through the IMM is accomplished by a group of mitochondrial Ca 2+ uptake transporters. Basically, three main mechanisms of Ca 2+ influx have been proposed ( Figure 1 ): (1) a mechanism that requires an electrogenic mitochondrial Ca 2+ uniporter multi-protein complex (MCU complex); (2) a so-called rapid mode (RaM); (3) a mechanism requiring the mitochondrial ryanodine receptor (mRyR) [ 7 , 10 , 12 , 13 , 38 ]; and (4) additionally, leucine zipper-EF-hand containing transmembrane protein (LETM1) could represent another Ca 2+ influx mechanism, but its role is still under discussion [ 61 , 62 , 63 , 64 ].…”

“…LETM1 (leucine zipper- EF-hand containing transmembrane protein, 70 kDa) is an integral mitochondrial inner membrane protein, usually co-localized with a mitochondrial matrix protein HSP60 [ 62 , 96 ]. The N-terminus of this protein is linked to the IMM via a transmembrane domain consisting of 3 proline residues, whereas the C-terminus extends to the mitochondrial matrix [ 62 , 63 , 97 ].…”

“…LETM1 (leucine zipper- EF-hand containing transmembrane protein, 70 kDa) is an integral mitochondrial inner membrane protein, usually co-localized with a mitochondrial matrix protein HSP60 [ 62 , 96 ]. The N-terminus of this protein is linked to the IMM via a transmembrane domain consisting of 3 proline residues, whereas the C-terminus extends to the mitochondrial matrix [ 62 , 63 , 97 ]. It was also demonstrated previously that LETM1 is an endogenous protein in HeLa cells, with a molecular weight of 83 kDa, and it has been assumed that it is initially produced as a cytosolic precursor with a presequence [ 62 , 96 , 98 , 99 ].…”