{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNUBPL, also known as huInd1 or Ind1 in model systems, encodes a mitochondrial assembly factor essential for the biogenesis of respiratory complex I. Multiple studies have demonstrated that NUBPL binds iron‐sulfur (Fe/S) clusters through a conserved CXXC motif and facilitates the incorporation of these cofactors into complex I subunits. Disruption of NUBPL function—through mutations or knockdown—leads to impaired assembly of complex I (often stalling at the Q module stage), loss of full matrix arm formation, and a marked reduction in enzyme activity. These findings were initially uncovered by candidate gene analyses and RNA interference experiments that revealed severe declines in complex I subunit levels and altered supercomplex organization when NUBPL/Ind1 was compromised."}, {"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": "\nAdditional research using yeast models and patient-derived cells has further detailed the role of NUBPL in complex I assembly. By mimicking patient mutations in the yeast homologue Ind1, researchers observed defects in the transition from assembly intermediates (especially within the Q module) to the fully assembled matrix arm, with associated cold sensitivity as a diagnostic phenotype. Moreover, rescued expression experiments confirmed that wild-type NUBPL could restore both complex I integrity and secondary complex III stability, with hints of an additional role in mitochondrial DNA translation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical function in mitochondrial energy metabolism, aberrant NUBPL expression has been implicated in broader pathological contexts. Overexpression of NUBPL in colorectal cancer correlates with enhanced cell migration, invasion, and the induction of epithelial–mesenchymal transition via ERK activation, suggesting a role in tumor metastasis. In addition, genome‐wide association studies have identified NUBPL as a candidate gene potentially mediating drug-induced QT prolongation, indicating that variations in NUBPL may also contribute to cardiac electrophysiological alterations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, clinical studies have expanded the phenotypic spectrum associated with NUBPL mutations, ranging from classical mitochondrial complex I deficiency and multisystemic disorders to specific leukodystrophies with distinct neuroradiological features. Such studies underscore the critical nature of NUBPL in both mitochondrial bioenergetics and cellular homeostasis, with its dysfunction resulting in a diverse array of clinical presentations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alex D Sheftel, Oliver Stehling, Antonio J Pierik, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Human Ind1 expression causes over-expression of E. coli beta-lactamase ampicillin resistance protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Expr Purif (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pep.2014.09.005"}], "href": "https://doi.org/10.1016/j.pep.2014.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25240856"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25240856"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Andrew E Maclean, Virginia E Kimonis, Janneke Balk "}, {"type": "b", "children": [{"type": "t", "text": "Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy247"}], "href": "https://doi.org/10.1093/hmg/ddy247"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29982452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29982452"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Margherita Protasoni, Claudio Bruno, Maria Alice Donati, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2019.11.003"}], "href": "https://doi.org/10.1016/j.ymgme.2019.11.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31787496"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31787496"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yuhui Wang, Nan Wu, Donglin Sun, et al. 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