Aars2, or mitochondrial alanyl-tRNA synthetase 2, is one of the aminoacyl-tRNA synthases (ARSs) that performs amino acid transportation and is involved in protein synthesis within mitochondria [2]. It is responsible for charging tRNA-Ala with alanine during mitochondrial translation [5]. Mutations in Aars2 have been associated with a variety of disorders, indicating its importance in normal biological function. Genetic models, such as gene-knockout (KO) or conditional-knockout (CKO) mouse models, can potentially shed light on its exact functions in vivo.

Mutations in Aars2 are linked to autosomal recessive leukodystrophy, characterized by cognitive decline, ataxia, spasticity, and Parkinsonism [1]. In a case report, a 21-year-old male with Aars2-related leukodystrophy had compound heterozygous mutations in the Aars2 gene [1]. The emerging neurological spectrum of Aars2-associated disorders includes movement disorders, cognitive impairment, corticospinal signs, behavioral or psychiatric features, and eye signs, often with imaging evidence of leukoencephalopathy [3]. Premature ovarian failure is also frequent in females with Aars2 defects [3,6]. Additionally, Aars2 is upregulated in multiple cancers and may serve as a novel biomarker for prognosis and immunotherapy, with its deficiency inhibiting cell proliferation and migration in hepatocellular carcinoma (HCC) [2]. Aars2 also functions as a protein lysine lactyltransferase, and hypoxia-induced Aars2 accumulation can lactylate certain enzymes to limit oxidative phosphorylation [4]. In congenital cardiomyopathy, PCBP1 regulates the alternative splicing of Aars2, and loss of Pcbp1 or exon-16 skipping in Aars2 leads to heart developmental defects [5].

In conclusion, Aars2 is essential for mitochondrial protein synthesis and has a wide-reaching impact on various biological processes. Model-based research, especially KO/CKO mouse models, could potentially further clarify its role in diseases such as leukodystrophy, neurological disorders, ovarian insufficiency, cancer, and congenital cardiomyopathy. Understanding Aars2 provides insights into the underlying mechanisms of these diseases and may contribute to the development of new therapeutic strategies.