MetRS-m (Drosophila melanogaster, Q9VFL5) - manual literature summary

No deep-research provider was available in this session; this summary was compiled by hand from
cached publications and the UniProt record.

Identity

• MetRS-m (synonyms Aats-met, Aats-met-m; CG31322/CG8684; FBgn0027083; GeneID 41733) encodes the
  mitochondrial methionyl-tRNA synthetase, 582 aa, with a predicted mitochondrial transit peptide
  (residues 1-95) [file:DROME/MetRS-m/MetRS-m-uniprot.txt "TRANSIT 1..95"].
• Class I aminoacyl-tRNA synthetase with HIGH (27-37) and KMSKS (317-321) motifs; NCBIfam TIGR00398 metG;
  PANTHER PTHR43326:SF1 (METHIONINE--TRNA LIGASE, MITOCHONDRIAL).
• Ortholog of human MARS2; "Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA
  synthetase, with 44% identity and 75% similarity to its human orthologue MARS2" PMID:22448145.
• Listed as the single mitochondrial MetRS in the fly aaRS catalogue (CG31322, M, MARS2 ortholog)
  PMID:26761199.

Genetics (PMID:22448145, Bayat et al. 2012, full text)

• Lethal complementation group (alleles HV = V42D, FB = S224L) plus a piggyBac insertion; allelic series
  Df>PB>FB>HV.
• Ubiquitous expression of fly Aats-met or human MARS2 cDNA rescued lethality and ERG defects: "The fly
  and human cDNAs rescued the lethality associated with FB/Df and HV/Df, the strongest allelic
  combinations."
• Flag-tagged human MARS2 co-localizes with mito-GFP in larval neurons (localization of the human
  ortholog, not of the fly protein itself).
• Mutants: progressive photoreceptor degeneration, reduced cell proliferation, upregulated UPRmt (Hsp60),
  reduced Complex I activity, reduced aconitase activity (ROS), phenotypes suppressed by antioxidants.
• Authors treat it as a mitochondrial translation factor: "Since Aats-met/MARS2 is a mitochondrial
  translation factor". Mitochondrial translation defects were measured in ARSAL patient cells (human),
  not in the fly.
• No direct enzymatic assay of the fly protein is reported.

Glial lipid droplets (PMID:25594180, Liu et al. 2015)

• Aats-met mutant clones and neuronal knockdown cause glial lipid droplet accumulation before
  neurodegeneration, downstream of ROS/JNK/SREBP; these are indirect consequences of mitochondrial
  dysfunction, not functions of the enzyme.

Interpretation

• Core activity: methionine-tRNA ligase activity (GO:0004825) charging mitochondrial tRNA(Met),
  supporting mitochondrial translation (GO:0070127), in the mitochondrial matrix. Evidence is
  homology (strong, orthology with MARS2 + domain architecture) plus cross-species genetic rescue.