{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman mitochondrial tyrosyl‐tRNA synthetase (YARS2) plays a central role in mitochondrial protein synthesis by catalyzing the attachment of tyrosine to its cognate mitochondrial tRNA. Detailed biochemical and structural characterizations have shown that YARS2 displays dual sequence features reminiscent of both eubacterial and archaeal tyrosyl-tRNA synthetases, and it lacks strict discrimination toward tRNA identity elements. Crystallographic studies further reveal an active, dimeric enzyme with a conserved catalytic domain and unique surface bulges that likely contribute to its substrate interactions and overall function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in YARS2 have been implicated in specific mitochondrial disorders, most notably manifesting as myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Investigations of patients harboring mutations—such as p.Phe52Leu, p.Gly46Asp, and p.Gly191Val—indicate that these variants lead to reduced levels or impaired kinetics of the enzyme, consequently diminishing mitochondrial protein synthesis and respiratory chain complex activities. In addition, systematic screenings have expanded the clinical spectrum, revealing that YARS2 mutations can result in variable phenotypes ranging from typical MLASA presentations to isolated congenital sideroblastic anemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its primary role in mitochondrial translation, YARS2 functions as a nuclear modifier gene in disorders caused by mtDNA mutations. Studies have demonstrated that the presence of YARS2 variants—most notably the p.Gly191Val change—can exacerbate mitochondrial dysfunction when coexisting with classical LHON-associated mutations (such as m.11778G>A) or tRNA alterations. These synergistic effects compromise tRNA metabolism and mitochondrial translation, leading to severe deficits in respiratory chain functions in sensitive cell types like retinal ganglion cells and auditory structures, effects that can be alleviated upon genetic correction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its involvement in inherited mitochondrial diseases, aberrant YARS2 expression has been linked to oncogenesis. In colorectal cancer, elevated YARS2 levels promote tumor cell proliferation and migration, whereas its knockdown results in decreased mitochondrial ATP synthesis, reduced oxygen consumption, and increased reactive oxygen species—thereby enhancing sensitivity to chemotherapeutic agents such as 5-fluorouracil."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"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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"}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human mitochondrial tyrosyl-tRNA synthetase reveals common and idiosyncratic features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2007.09.018"}], "href": "https://doi.org/10.1016/j.str.2007.09.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17997975"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17997975"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lisa G Riley, Sandra Cooper, Peter Hickey, et al. 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