The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

Abstract

Respiring mitochondria maintain a membrane potential (⌬⌿) 1 of Ϫ150 to Ϫ180 mV (⌬⌿, inside negative). This high ⌬⌿ constitutes a large driving force for the electrophoretic influx of cations, either through specific channels or by diffusion through the membrane. Several cation channels have been characterized physiologically (reviewed in Refs. 1 and 2), and recently, a single one has been identified molecularly (3). These transport systems seem to have intrinsic control mechanisms which ensure that the matrix cation concentrations stay within physiological ranges, far below chemical equilibrium.Diffusive permeability of the inner mitochondrial membrane to ions is generally low but physiologically significant, as it lowers the pH gradient and membrane potential. Moreover, if not counteracted by extrusion, steadily increasing concentrations of matrix cations (and of compensating anions) will lead to an imbalance of osmotic pressure across the inner mitochondrial membrane. As a consequence, water will pass through the membrane, causing excessive swelling and eventual rupture of the organelle (1, 2, 4).As first proposed by P. Mitchell (5), mitochondria have carrier systems allowing the electroneutral exchange of cations against H ϩ (and anions against OH Ϫ ). These exchangers counteract the ⌬⌿-driven cation leakage of the membrane and also cation imbalances due to changes in mitochondrial physiology. Mitochondrial cation distribution is, therefore, a steady state, in which the accumulation ratio is modulated by the relative rates of cation influx and efflux by means of separate pathways.Many physiological studies have been devoted to cation/H ϩ exchange systems (reviewed in Ref.

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…LETM1 encodes a ubiquitously expressed leucine zipper-EF-handcontaining transmembrane 1 protein 18 with intracellular localization to mitochondria 36,37 and the ER. 38 Its cellular function as an ion exchanger [37][38][39][40][41] suggests potential roles in cell signaling and energy production.…”

“…38 Its cellular function as an ion exchanger [37][38][39][40][41] suggests potential roles in cell signaling and energy production. In flies and worms, LETM1 loss-of-function causes severe growth restriction and decreased viability.…”

Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy

“…Its product is an integral protein of the inner mitochondrial membrane, and is well conserved among all eukaryotes. 6 Hemizygous deletion in humans has been invoked as causing a major part of the Wolf-Hirschhorn disease phenotype. 7 The presence of a putative EF Ca 2 þ binding hand domain within almost all Mdm38p homologues suggested a role for Mdm38p in mitochondrial Ca 2 þ homeostasis and morphology.…”

“…Mutants deleted for this gene have functional defects of mitochondria, reduced growth of cells on non-fermentable substrate (petite phenotype), a nearly complete loss of mitochondrial K þ (Na þ )/H þ exchange activity, high K þ matrix content, low membrane potential (Dc), and dramatically increased volume. 6,9 Recently, Frazier et al (2006) noted reduced amounts of certain mitochondrially encoded proteins in the inner membrane despite their translation efficiency being unchanged. They found that protein A-tagged Mdm38p formed complexes with mitochondrial ribosomes, and suggested that the reduced amount of some of the mitochondrially encoded proteins of complexes III, IV, and V resulted from the lack of Mdm38p interacting with mitochondrial ribosomes to mediate membrane insertion of several proteins of nuclear and mitochondrial origin.…”

“…Yeast strains disrupted for the MDM38 gene (mdm38D) exhibit a growth defect on non-fermentable substrate (petite phenotype) and altered mitochondrial morphology, 5 reduced amounts of certain mitochondrially encoded proteins, reduced Dc 6,13 and a near total loss of mitochondrial K þ /H þ exchange activity associated with increased K þ content and osmotic swelling. 6,9 Figure 1 presents the pattern of mitochondrially translated proteins obtained by incubation of wild type and mdm38D cells with labeled methionine in the presence of cycloheximide. Consistent with previous observations, 13 we observe a reduction in abundance of Cox2, Cob, and Cox3, but no apparent changes in ATP synthase proteins.…”