{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The gene DNM1L encodes a large GTPase—dynamin‐related protein 1 (DRP1)—that plays a central role in regulating mitochondrial (and peroxisomal) fission, a critical process for maintaining organelle morphology, quality control, and cellular homeostasis. DRP1 is normally present in the cytosol and is recruited to the mitochondrial outer membrane by several adaptor proteins (such as hFis1, Mff, MiD49/MiD51, and FUNDC1) to execute fission through GTP hydrolysis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n Its recruitment and enzymatic activity are tightly controlled by post‐translational modifications. For example, sustained cytosolic Ca²⁺ levels activate calcineurin, which dephosphorylates DRP1 and promotes its translocation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", whereas stress signals such as nitric oxide can lead to S‐nitrosylation of DRP1 that triggers pathological fission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, DRP1 activity is modulated by phosphorylation at conserved residues (for example, serine 656 or serine 616), which influences mitochondrial fragmentation, apoptotic sensitivity, and cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Dysregulation of DRP1/ DNM1L function has been implicated in a variety of pathophysiological states. Aberrant DRP1 activation leads to excessive mitochondrial fragmentation, which contributes to the accumulation of dysfunctional mitochondria and plays a role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Huntington’s disease—where mutant proteins or amyloid‐β interact directly with DRP1—, as well as in acute kidney injury and cardiac dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": " In cancer and cell cycle regulation, alterations in DRP1 activity—often via oncogenic signals or altered phosphorylation—affect mitochondrial dynamics and contribute to metabolic reprogramming and proliferative capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its central role in mitochondrial division, DNM1L/DRP1 also participates in quality‐control pathways such as mitophagy and in peroxisomal fission. Its interaction with proteins like Parkin—where Parkin-mediated ubiquitination of DRP1 can modulate its levels and activity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "—and with factors such as Bnip3, which facilitate DRP1 translocation and autophagic removal of damaged organelles"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", further underscores the versatility of DNM1L in mitochondrial homeostasis. Moreover, studies demonstrating that genetic or pharmacological inhibition of DRP1 (for example, with dominant-negative mutants or small-molecule inhibitors like mdivi-1) can rescue mitochondrial dysfunction and reduce apoptosis highlight the therapeutic potential of targeting DRP1-mediated fission in disease settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish DNM1L/DRP1 as a master regulator of mitochondrial and peroxisomal dynamics whose versatile control by upstream signaling pathways and binding partners ensures proper organelle distribution, metabolic efficiency, and cellular integrity. Disruption of these processes through aberrant DRP1 activation or inhibition is a recurring theme in neurodegeneration, cardiovascular injury, metabolic disorders, and oncogenic transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "23"}]}, {"type": "t", "text": " \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Oliver C Losón, Zhiyin Song, Hsiuchen Chen, et al. 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