LETM1 and mitochondrial calcium homeostasis: A controversial but critical role in cellular function and disease

Abstract

Calcium is a pivotal ion in cellular signaling, orchestrating pathways that support both cell survival and cell death. The mitochondria and endoplasmic reticulum are the principal organelles responsible for Ca²⁺ storage and play fundamental roles in maintaining intracellular Ca²⁺ homeostasis. The mitochondrial outer membrane (MOM) acts as a selective barrier that regulates the exchange of metabolites and other essential molecules necessary for mitochondrial function. This tightly regulated exchange depends on specific proteins, such as the voltage-dependent anion channel (VDAC), which serves as a key mediator of metabolite flux across the MOM. The mitochondrial Ca²⁺ uniporter (MCU) and the electrogenic Na⁺/Li⁺/Ca²⁺ exchanger (NCLX) represents the best-characterized mechanisms governing mitochondrial Ca²⁺ uptake and efflux, respectively. The leucine zipper EF-hand–containing transmembrane protein 1 (LETM1), localized to the inner mitochondrial membrane (IMM), has also been implicated in the regulation of mitochondrial Ca²⁺ homeostasis. This IMM protein was initially identified in association with Wolf–Hirschhorn Syndrome (WHS), a rare chromosomal disorder characterized by microcephaly, growth retardation, intellectual disability, and early-onset epileptic seizures. Approximately sixteen years ago, LETM1 was proposed to mediate K⁺/H⁺ exchange across the IMM. However, subsequent studies suggested an alternative function as a Ca²⁺/H⁺ exchanger, leading to an ongoing debate regarding its exact physiological role. Despite this controversy, the crucial contribution of LETM1 to mitochondrial physiology is widely acknowledged. LETM1 is considered an essential gene, and its dysfunction has been associated with a spectrum of pathological conditions, including Parkinson’s disease, obesity, and cancer.