{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPantothenate kinase 2 (PANK2) is a mitochondrial enzyme that catalyzes the first, rate‐limiting step in the de novo biosynthesis of coenzyme A (CoA) by phosphorylating pantothenate (vitamin B₅). Unlike other pantothenate kinase isoforms, PANK2 contains a mitochondrial-targeting sequence and undergoes sequential proteolytic processing to yield long‐lived, mature isoforms that are central to mitochondrial lipid and energy metabolism. Its activity is tightly regulated by feedback inhibition in response to acyl-CoA species rather than CoA per se, highlighting a unique allosteric regulation mechanism essential for maintaining CoA homeostasis in neurons and other tissues involved in high-energy and lipid-dependent processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA number of studies have established that mutations in the PANK2 gene lead to pantothenate kinase-associated neurodegeneration (PKAN), a prominent subtype of neurodegeneration with brain iron accumulation (NBIA). Disease-associated point mutations can result in reduced catalytic activity, defective protein folding, and altered intramitochondrial processing. In some cases, mutant proteins retain near-normal enzymatic activity yet still trigger pathogenesis via disrupted regulation or stability. Such alterations may perturb CoA synthesis, thereby impacting mitochondrial function, lipid metabolism (including bile acid conjugation), and even erythrocyte membrane properties, which in turn contribute to neuronal dysfunction. These insights have also raised the therapeutic possibility of supplementing CoA or its precursors to counteract the metabolic deficits."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, PANK2 dysfunction manifests as a spectrum of neurodegenerative conditions characterized by extrapyramidal symptoms such as dystonia, parkinsonism, and cognitive deficits, often accompanied by distinctive iron deposition in the basal ganglia. Investigations in patient-derived cellular models, animal models, and post-mortem studies have elucidated that mitochondrial defects, increased oxidative stress, and disrupted NADH/FADH₂ substrate supply are central to disease progression. These findings underscore the genetic and biochemical heterogeneity underlying PKAN and related NBIA disorders, reinforce the significance of mitochondrial lipid metabolism in neuronal survival, and point to the potential of targeted therapeutic interventions—ranging from deep brain stimulation to nutritional supplementation—as avenues for ameliorating clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Monika B Hartig, Konstanze Hörtnagel, Barbara Garavaglia, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.4265-04.2005"}], "href": "https://doi.org/10.1523/JNEUROSCI.4265-04.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15659606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15659606"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Konstanze Hörtnagel, Holger Prokisch, Thomas Meitinger "}, {"type": "b", "children": [{"type": "t", "text": "An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddg026"}], "href": "https://doi.org/10.1093/hmg/ddg026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12554685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12554685"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Madhavi Thomas, Susan J Hayflick, Joseph Jankovic "}, {"type": "b", "children": [{"type": "t", "text": "Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mov Disord (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mds.10650"}], "href": "https://doi.org/10.1002/mds.10650"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14743358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14743358"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Valerio Leoni, Laura Strittmatter, Giovanna Zorzi, et al. 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