{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDARS2 encodes the mitochondrial aspartyl-tRNA synthetase (mtAspRS), a key enzyme that catalyzes the attachment of aspartate to its cognate tRNA. This aminoacylation step is essential for mitochondrial protein synthesis, ensuring the proper translation of the 13 proteins encoded by the mitochondrial genome. Structural and biochemical analyses reveal that mtAspRS possesses unique features—such as an enlarged catalytic groove and high affinity for its tRNA substrates—that enable it to function efficiently despite the evolutionary divergence of mitochondrial tRNAs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in DARS2 impair the normal function of mtAspRS, leading to reduced aminoacylation activity, altered protein stability, compromised dimerization, and aberrant mRNA splicing (notably affecting exon 3). These molecular defects result in a marked decrease in mitochondrial translation efficiency and function. Clinically, such impairments manifest as leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)—a disorder characterized by progressive cerebellar ataxia, spasticity, dorsal column dysfunction, and sometimes cognitive decline. Furthermore, cell‐type–specific defects, including differences in splicing efficiency in neural tissues, help explain the selective vulnerability of particular white matter tracts observed in patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its fundamental role in mitochondrial translation, emerging evidence suggests that alterations in DARS2 expression may be linked to oncogenic processes. Overexpression of DARS2 has been observed in several tumor types, including lung adenocarcinoma, where it appears to correlate with disease stage and prognosis and may influence tumor cell proliferation and metabolic reprogramming. Although the precise molecular mechanisms remain to be fully elucidated, these observations point to a potential role for DARS2 in cancer pathophysiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast, investigations into common genetic variants of mitochondrial proteins, including DARS2, have not identified significant links with metabolic disorders such as type II diabetes mellitus, suggesting that the pathogenic impact of DARS2 alterations is more confined to neurological and oncogenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Luc Bonnefond, Aurélie Fender, Joëlle Rudinger-Thirion, et al. 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