LYRM protein (Leucine-Tyrosine-Arginine motif) also known as LYRMs, are a superfamily of small (11–22 kDa), basic, predominantly mitochondrial proteins found exclusively in eukaryotes and named after their conserved LYR-like motif near the N-terminus. They function as accessory subunits or assembly factors of OXPHOS complexes I, II, III and V and play essential roles in iron–sulfur (Fe–S) cluster biogenesis, mitochondrial translation, electron transfer flavoprotein (ETF) function, and acetate metabolism. Most LYRM proteins depend on mitochondrial fatty acid synthesis (mtFAS) for their function, as they are allosterically activated by binding to acylated mitochondrial acyl carrier protein (acyl-mtACP). It has been proposed that this mechanism evolved to protect cells from the toxic interaction of iron and oxygen.
Species distribution LYRM proteins are found exclusively in eukaryotes, but they differ between species. While LYRM proteins have been lost in anaerobic eukaryotes or are retained only in the form of LYRM4, twelve LYRM proteins occur in humans.
Human paralogs At least 12 LYRM proteins have been identified in humans (2019):
Subcellular distribution With the exception of LYRM3 and LYRM6, which are embedded within mitochondrial Complex I, LYRM proteins are soluble matrix-located proteins. They are synthesized in the cytosol by ribosomes after being transcribed from nuclear DNA, and are then imported into the mitochondria. Some members have also been identified in the cytosol and nucleus.
Structure LYRM proteins constitute a conserved family of small mitochondrial proteins defined by sequence homology to the Complex1_LYR-like superfamily (Pfam clan CL0491, which was identified by bioinformatic analysis and curated by P. Coggill (EMBL-EBI). The family was originally defined based on LYRM4, which stabilizes the cysteine desulfurase NFS1 within the mitochondrial iron–sulfur cluster (ISC) assembly machinery. The presence of an LYR tripeptide alone is not sufficient to classify a protein as an LYRM, as additional conserved amino acid residues must also be present. Members of this family share the following characteristic features:
Sequence features: a conserved LYR-like motif near the N-terminus (e.g. LYR, LYK, LFK, TFR), additional conserved amino acid residues downstream of the motif: basic residues, particularly arginine (R) and lysine (K), a highly conserved phenylalanine (F) residue, in some subfamilies, additional residues including tyrosine (Y) and glycine (G) at the C-terminus, Structural features: structural homology characterized by a conserved three-α-helix bundle, a hydrophobic channel formed by the three-α-helix bundle, accommodating the fatty acyl chain of acylated mtACP (except FMC1), General properties: a small protein size (11–22 kDa), a basic isoelectric point (pI ≈ 9–11),
Function The family was originally defined based on LYRM4, which stabilizes the cysteine desulfurase NFS1 within the mitochondrial iron–sulfur cluster (ISC) assembly machinery. All LYRM proteins have in common that they are found in mitochondrial target complexes that contain iron–sulfur clusters, synthesize them, or are functionally linked to them, such as the electron transfer protein and the mitochondrial ribosome. The only exception is FMC1, which acts at a target complex lacking iron–sulfur clusters, complex V, although this complex has been linked to mitochondrial iron uptake. These features distinguish LYRM proteins from the broader term "LYR proteins", which has been used by some authors in the past for proteins that contain an LYR tripeptide—a motif frequently found in mitochondrial proteins such as SDHB, NDUFAF3, or mitochondrial ribosomal proteins—but that lack the additional defining characteristics of the LYRM family.
Iron–sulfur cluster biogensis In eukaryotes, iron–sulfur (Fe–S) clusters serve as versatile cofactors in redox reactions, electron transport, enzyme catalysis, regulation of gene expression, and DNA repair. They are assembled on the ISCU scaffold protein, with iron donated by frataxin and sulfur provided by the NFS1–LYRM4 complex. This complex binds acyl-mtACP via LYRM4, and this interaction stabilizes the otherwise degradation-prone complex. Once formed, Fe–S clusters are transferred to target proteins by a Fe–S transfer complex composed of ISCU, the co-chaperone HSC20, and the chaperone HSPA9. The incorporation of iron–sulfur clusters into OXPHOS complexes II and III with the help of other LYRM proteins is covered below under "OXPHOS complex assembly".
OXPHOS complex assembly The assembly of these complexes depends on a tightly regulated and coordinated process involving transcription and translation of both nuclear- and mitochondrial-encoded subunits, import and assembly of individual subunits, and maturation through the insertion of essential cofactors such as iron–sulfur clusters. OXPHOS complexes can further assemble into higher-order structures known as supercomplexes, whose formation and stability are influenced by interactions between acylated mtACP and LYRM proteins.
Complex I (NADH:ubiquinone oxidoreductase) Three LYRM proteins—LYRM3, LYRM6, and LYRM2—are known to be associated with Complex I. The first complex of the respiratory chain couples NADH oxidation and ubiquinone reduction to proton pumping across the inner mitochondrial membrane and constitutes the largest single contributor to the proton motive force driving ATP synthesis. Under certain conditions, the reaction can reverse, resulting in the reduction of NAD+. LYRM3 is an integral accessory subunit of Complex I, positioned in the distal proton-translocating module PD of the membrane arm. It forms a stable heterodimer with the neighboring mtACP, contributing to the stability and assembly of Complex I. LYRM6 is also an integral accessory subunit of Complex I. It binds near the critical interface between the matrix arm (Q module) and the membrane arm (P module) of Complex I, forming a heterodimer with mtACP. Two adjacent loops of LYRM6 interact directly with central subunits of Complex I, helping stabilize this interface. In particular, LYRM6 plays a key role in stabilizing the TMH1-2 loop of subunit ND3, a structural element essential for the proton pumping mechanism. LYRM2 is located in mitochondria, directly interacts with Complex I and increases its activity.
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