{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cardiolipin synthase 1 (CRLS1) is the mitochondrial enzyme that catalyzes the final step in the biosynthesis of cardiolipin, a unique phospholipid essential for maintaining the structure and function of the inner mitochondrial membrane. By governing cardiolipin production, CRLS1 plays a central role in organizing respiratory chain supercomplexes, preserving mitochondrial morphology, and ensuring efficient energy production. Reduced CRLS1 expression or activity has been associated with defective cardiolipin remodeling—leading to impaired mitochondrial dynamics, altered bioenergetics, and increased susceptibility to stress—which in turn contributes to a wide range of pathological conditions including mitochondrial encephalopathies, neuromuscular disorders, metabolic diseases, and certain cancers. For example, diminished CRLS1 function has been linked to aberrant mitochondrial structure in neurodegenerative syndromes and to an increased burden of metabolic derangements in nonalcoholic steatohepatitis and heart failure, while its modulation via noncoding RNAs affects tumor progression in hepatocellular carcinoma and non‐small cell lung cancer (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " Moreover, genetic variants and experimental models that impair CRLS1 activity have demonstrated its indispensable role in proper embryonic development and mitochondrial homeostasis, as well as its involvement in regulating inflammation and insulin sensitivity in metabolically active tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " In the context of cancer, higher CRLS1 expression has been correlated with improved prognostic outcomes, suggesting that maintenance of cardiolipin integrity may suppress oncogenic metabolic reprogramming."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, conditional knockout studies underline the critical importance of CRLS1 in tissues with high energy demand, as its loss impairs mitochondrial respiration and calcium handling, ultimately compromising cellular viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Collectively, these findings position CRLS1 as a central node linking mitochondrial lipid remodeling to cellular energy homeostasis and viability, and they underscore its potential as a therapeutic target in diseases characterized by mitochondrial dysfunction and metabolic imbalance.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Riekelt H Houtkooper, Hana Akbari, Henk van Lenthe, et al. 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