Molecular Mechanisms of Leucine Zipper EF-Hand Containing Transmembrane Protein-1 Function in Health and Disease.

Qi-Tong Lin,Peter Stathopulos

doi:10.3390/ijms20020286

Abstract

Mitochondrial calcium (Ca2+) uptake shapes cytosolic Ca2+ signals involved in countless cellular processes and more directly regulates numerous mitochondrial functions including ATP production, autophagy and apoptosis. Given the intimate link to both life and death processes, it is imperative that mitochondria tightly regulate intramitochondrial Ca2+ levels with a high degree of precision. Among the Ca2+ handling tools of mitochondria, the leucine zipper EF-hand containing transmembrane protein-1 (LETM1) is a transporter protein localized to the inner mitochondrial membrane shown to constitute a Ca2+/H+ exchanger activity. The significance of LETM1 to mitochondrial Ca2+ regulation is evident from Wolf-Hirschhorn syndrome patients that harbor a haplodeficiency in LETM1 expression, leading to dysfunctional mitochondrial Ca2+ handling and from numerous types of cancer cells that show an upregulation of LETM1 expression. Despite the significance of LETM1 to cell physiology and pathophysiology, the molecular mechanisms of LETM1 function remain poorly defined. In this review, we aim to provide an overview of the current understanding of LETM1 structure and function and pinpoint the knowledge gaps that need to be filled in order to unravel the underlying mechanistic basis for LETM1 function.

Highlights

Calcium (Ca2+) is a divalent cation that regulates many facets of cell physiology such as gene expression, muscular contraction, fertilization, proliferation and bioenergetics, to name a few
We aim to provide an overview of the current understanding of leucine zipper EF-hand containing transmembrane protein-1 (LETM1) structure and function, and identify important new research questions which are needed to unravel the underlying mechanistic basis for LETM1 function
The fact that EF-hands are well conserved amongst LETM1 orthologs and the direct impact they have on mitochondrial Ca2+ transport as assessed via mutations and deletions showcase the importance of the EF-hand in LETM1 function and highlights a functionally critical area of LETM1 that remains structurally unresolved at high resolution

Summary

Introduction

Calcium (Ca2+) is a divalent cation that regulates many facets of cell physiology such as gene expression, muscular contraction, fertilization, proliferation and bioenergetics, to name a few. The uptake of cations such as Ca2+ and potassium (K+) (see below) into mitochondria is driven by the large negative membrane potential across the inner mitochondrial membrane (IMM) (i.e., ~−180 mV in the matrix relative to the intermembrane space (IMS)) [28,29,30]. The mPTP-induced non-selective flow of ions and small molecules in both directions increase osmotic pressure and further decreases the membrane potential, leading to mitochondria swelling, disruption in oxidative phosphorylation, and driving cell death [43,45,46]. The N-terminal matrix domain contains a divalent cation binding site that regulates MCU architecture and function, in a feedback-like mechanism observed for many other Ca2+ channels [54,55]. We aim to provide an overview of the current understanding of LETM1 structure and function, and identify important new research questions which are needed to unravel the underlying mechanistic basis for LETM1 function

The LETM1 Protein Family

The Role of LETM1 in Mitochondrial Physiology

LETM1 Protein Structure and Assembly

Conclusions