LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling

Abstract

Nearly 2 decades since its discovery as one of the genes responsible for the Wolf-Hirschhorn Syndrome (WHS), the primary function of the leucine-zipper EF-hand containing transmembrane 1 (LETM1) protein in the inner mitochondrial membrane (IMM) or the mechanism by which it regulates mitochondrial Ca2+ handling is unresolved. Meanwhile, LETM1 has been associated with the regulation of fundamental cellular processes, such as development, cellular respiration and metabolism, and apoptosis. This mini-review summarizes the diversity of cellular functions impacted by LETM1 and highlights the multiple roles of LETM1 in health and disease.

Altered Functional Mitochondrial Protein Levels in Plasma Neuron-Derived Extracellular Vesicles of Patients With Gadolinium Deposition

“…Inner mitochondrial membrane levels of LETM-1, a calcium channel/calcium channel enhancer of unclear mechanisms involved in calcium homeostasis, were significantly lower in GDD/GSC patients than controls. This may be attributable to an effect of Gd on the LETM-1 role in Ca ++ fluxes directly or indirectly by influencing LETM-1 actions in maintaining mitochondrial membrane structure and respiratory functions ( Natarajan et al, 2021 ). Ca++ fluxes across cellular and mitochondrial membranes are critical to a large number of physiological products including mitochondrial energy production ( Feng et al, 2010 ) and to muscle function and fatigue ( Eshima et al, 2014 ).…”

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

“…In addition to its contribution to the Δp driving the ATP synthase, the H + gradient generated in this manner drives import of inorganic phosphate for ATP synthesis via a Pi-H + cotransport system of the SLC25 family, and electroneutral import of Ca 2+ , Na + , and K + across the IMM, via H + exchange with Ca 2+ , Na + , and K + (for a review, see [ 79 ]). While this transporter has been a topic of controversy, the mitochondrial Ca 2+ /H + exchanger is most probably encoded by LETM1 [ 80 , 81 ]. LETM1 appears to directly sense both H + and Ca 2+ [ 82 ] and to play transport-unrelated roles in signaling, including its physical anchoring to the mitochondrial ribosome protein L36 [ 83 ].…”

“…SLC9A1 (NHE1), which predominantly localizes to the plasma membrane, was detected in cardiomyocyte mitochondrial fractions [ 85 ], and also the related transporter SLC9B2 (NHA2) appears mitochondrially localized in some cells [ 86 , 87 ]. The molecular identity of the mitochondrial K + /H + exchange mechanism remains highly contentious, and it remains possible that also this function involves LETM1 [ 81 , 88 ]. The mitochondrial uncoupling protein UCP1 is also a H + channel, albeit this isoform is specific to brown adipose tissue [ 89 ], and of course also the highly permeable mPTP carries H + .…”

TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy

“…These findings suggest that alternative mechanisms for Ca 2+ entry may exist ( Murphy et al, 2014 ; Wüst et al, 2017 ) such as the Ca 2+ /2H + exchanger (CHE) leucine zipper and EF-hand containing transmembrane protein 1 (LETM1), which can work in both directions ( Jiang et al, 2009 ). LETM1 apparently also mediates K + /H + exchange (KHE) ( Nowikovsky et al, 2004 ; Natarajan et al, 2021 ), and the question which ion is transported when and in which direction is still largely unsolved. As the ion with the highest intracellular concentration, excessive K + flux into the mitochondrial matrix elicits osmotic effects and thus causes H 2 O influx into the mitochondrial matrix, triggering mitochondrial swelling.…”