{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:39:02Z","timestamp":1785904742889,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,17]]},"group-title":"In Review","reference-count":78,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,7]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  The mitochondrial phosphatase PPTC7 has emerged as a potent regulator of metabolism and mitophagy as its global knockout leads to perinatal lethality in mice. However, no known Mendelian diseases have been linked to\n                  <italic>PPTC7<\/italic>\n                  deficiency, rendering its role in human pathophysiology unclear. Here, we identify two independent homozygous variants in\n                  <italic>PPTC7<\/italic>\n                  : a missense variant, p.D158N, and a duplication variant (c.*57dup) within the 3` untranslated region (UTR). These variants were detected in three patients from two unrelated families presenting with a primary mitochondrial disease characterized by hypomyelinating leukodystrophy, recurrent metabolic and lactic acidosis, and anemia with immune dysregulation. Patient samples, including plasma and primary fibroblasts, showed robust metabolic and mitochondrial dysfunction, with substantial phenotypic overlap with\n                  <italic>Pptc7<\/italic>\n                  knockout murine fibroblast models.\n                  <italic>PPTC7<\/italic>\n                  patient fibroblasts carrying the p.D158N variant and CRISPR-knocked in cells to model the 3`UTR variant showed hallmarks of excessive BNIP3- and NIX-mediated mitophagy, including aberrant mitochondrial morphology, diminished mitochondrial protein expression, and increased mt-Keima flux. Critically, increased mitophagy in these cellular models was rescued by exogenous PPTC7 expression, confirming dysfunction derives from loss of this mitochondrial phosphatase. Mechanistically, we found that the p.D158N variant, affecting a highly conserved residue, disrupts metal binding to compromise both the enzymatic phosphatase function of PPTC7 as well as its negative regulation of BNIP3 and NIX. Collectively, these data provide the first known cases with a recessive inborn error of mitophagy due to PPTC7 deficiency and underscore the importance of this mitochondrial phosphatase in maintaining metabolic health and balanced mitophagy.\n                <\/p>","DOI":"10.21203\/rs.3.rs-8815446\/v1","type":"posted-content","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T16:13:57Z","timestamp":1771344837000},"source":"Crossref","is-referenced-by-count":2,"title":["Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5162-4807","authenticated-orcid":false,"given":"Keri-Lyn","family":"Kozul","sequence":"first","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"AlAsmari","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa","family":"Alharby","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Zakzouk","sequence":"additional","affiliation":[{"name":"Prince Sultan Military Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-6989","authenticated-orcid":false,"given":"Youmian","family":"Yan","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziza","family":"Mushiba","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar","family":"Alhamad","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-8217","authenticated-orcid":false,"given":"Emily","family":"Harrelson","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2213-9890","authenticated-orcid":false,"given":"Maya","family":"Ayach","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-3506","authenticated-orcid":false,"given":"Kevin","family":"Cho","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Zahid","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-2299","authenticated-orcid":false,"given":"Francisca De Luna","family":"Vitorino","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-2595","authenticated-orcid":false,"given":"Richard","family":"Searfoss","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0008-7815","authenticated-orcid":false,"given":"Xingyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed A.","family":"Saleh","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Latif","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianjie","family":"Wei","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Aldawood","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila","family":"Alsuhaibani","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Abdulhafith","family":"Bafail","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Menezes","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manar","family":"Samman","sequence":"additional","affiliation":[{"name":"Ministry of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-3093","authenticated-orcid":false,"given":"Hannah","family":"Pletcher","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Sandokji","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa","family":"Borhan","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Lochetto","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9754-9443","authenticated-orcid":false,"given":"Abrar","family":"Alamri","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wedad","family":"Mudayfin","sequence":"additional","affiliation":[{"name":"KAUST"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2713-1022","authenticated-orcid":false,"given":"Mazin","family":"Syed","sequence":"additional","affiliation":[{"name":"KAUST"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Shriver","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3596-4750","authenticated-orcid":false,"given":"Benjamin","family":"Garcia","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eissa","family":"Faqeih","sequence":"additional","affiliation":[{"name":"King Fahad Medical City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3748-6193","authenticated-orcid":false,"given":"Gary","family":"Patti","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5174-4005","authenticated-orcid":false,"given":"Natalie","family":"Niemi","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine in St. Louis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-395X","authenticated-orcid":false,"given":"Naif","family":"Almontashiri","sequence":"additional","affiliation":[{"name":"Taibah University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.cell.2012.02.035","article-title":"Mitochondria: In Sickness and in Health","volume":"148","author":"Nunnari J","year":"2012","unstructured":"Nunnari J, Suomalainen A (2012) Mitochondria: In Sickness and in Health. Cell 148:1145\u20131159","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1016\/j.molcel.2023.08.021","article-title":"Mitochondrial degradation: Mitophagy and beyond","volume":"83","author":"Uoselis L","year":"2023","unstructured":"Uoselis L, Nguyen TN, Lazarou M (2023) Mitochondrial degradation: Mitophagy and beyond. Mol Cell 83:3404\u20133420","journal-title":"Mol Cell"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nature08971","article-title":"Mutations of optineurin in amyotrophic lateral sclerosis","volume":"465","author":"Maruyama H","year":"2010","unstructured":"Maruyama H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223\u2013226","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1126\/science.1096284","article-title":"Hereditary Early-Onset Parkinson\u2019s Disease Caused by Mutations in PINK1","volume":"304","author":"Valente EM","year":"2004","unstructured":"Valente EM et al (2004) Hereditary Early-Onset Parkinson\u2019s Disease Caused by Mutations in PINK1. Science 304:1158\u20131160","journal-title":"Science"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1056\/NEJM200005253422103","article-title":"Association between Early-Onset Parkinson\u2019s Disease and Mutations in the Parkin Gene","volume":"342","author":"L\u00fccking CB","year":"2000","unstructured":"L\u00fccking CB et al (2000) Association between Early-Onset Parkinson\u2019s Disease and Mutations in the Parkin Gene. N Engl J Med 342:1560\u20131567","journal-title":"N Engl J Med"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1212\/WNL.51.3.890","article-title":"Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q","volume":"51","author":"Mori H","year":"1998","unstructured":"Mori H et al (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51:890\u2013892","journal-title":"Neurology"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1001\/archneur.65.4.467","article-title":"Risk of Parkinson Disease in Carriers of Parkin Mutations: Estimation Using the Kin-Cohort Method","volume":"65","author":"Wang Y","year":"2008","unstructured":"Wang Y et al (2008) Risk of Parkinson Disease in Carriers of Parkin Mutations: Estimation Using the Kin-Cohort Method. Arch Neurol 65:467\u2013474","journal-title":"Arch Neurol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1212\/01.WNL.0000142258.29304.FE","article-title":"PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations","volume":"63","author":"Hatano Y","year":"2004","unstructured":"Hatano Y et al (2004) PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations. Neurology 63:1482\u20131485","journal-title":"Neurology"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1212\/01.wnl.0000167546.39375.82","article-title":"Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes","volume":"65","author":"Bonifati V","year":"2005","unstructured":"Bonifati V et al (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65:87\u201395","journal-title":"Neurology"},{"key":"ref10","first-page":"1403","article-title":"SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis","volume":"70","author":"Ber I","year":"2013","unstructured":"Le Ber I et al (2013) SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA Neurol 70:1403\u20131410","journal-title":"JAMA Neurol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1212\/WNL.0b013e31826e25df","article-title":"SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"79","author":"Rubino E","year":"2012","unstructured":"Rubino E et al (2012) SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79:1556\u20131562","journal-title":"Neurology"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ajhg.2013.07.017","article-title":"Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance","volume":"93","author":"Bonnen PE","year":"2013","unstructured":"Bonnen PE et al (2013) Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance. Am J Hum Genet 93:471\u2013481","journal-title":"Am J Hum Genet"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.ajhg.2013.07.016","article-title":"Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy","volume":"93","author":"Gai X","year":"2013","unstructured":"Gai X et al (2013) Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy. Am J Hum Genet 93:482\u2013495","journal-title":"Am J Hum Genet"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"e112799","DOI":"10.15252\/embj.2022112799","article-title":"FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels","volume":"42","author":"Elcocks H","year":"2023","unstructured":"Elcocks H et al (2023) FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. EMBO J 42:e112799","journal-title":"EMBO J"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"e112767","DOI":"10.15252\/embj.2022112767","article-title":"FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors","volume":"42","author":"Nguyen-Dien GT","year":"2023","unstructured":"Nguyen-Dien GT et al (2023) FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors. EMBO J 42:e112767","journal-title":"EMBO J"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"e113033","DOI":"10.15252\/embj.2022113033","article-title":"A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease","volume":"42","author":"Cao Y","year":"2023","unstructured":"Cao Y et al (2023) A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease. EMBO J 42:e113033","journal-title":"EMBO J"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1038\/s41418-023-01205-1","article-title":"FBXL4 mutations cause excessive mitophagy via BNIP3\/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome","volume":"30","author":"Chen Y","year":"2023","unstructured":"Chen Y et al (2023) FBXL4 mutations cause excessive mitophagy via BNIP3\/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome. Cell Death Differ 30:2351\u20132363","journal-title":"Cell Death Differ"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"6431","DOI":"10.1038\/s41467-023-42069-w","article-title":"PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy","volume":"14","author":"Niemi NM","year":"2023","unstructured":"Niemi NM et al (2023) PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy. Nat Commun 14:6431","journal-title":"Nat Commun"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1038\/s44319-024-00181-y","article-title":"PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4","volume":"25","author":"Nguyen-Dien GT","year":"2024","unstructured":"Nguyen-Dien GT et al (2024) PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4. EMBO Rep 25:3324\u20133347","journal-title":"EMBO Rep"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.molcel.2023.11.038","article-title":"A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass","volume":"84","author":"Sun Y","year":"2024","unstructured":"Sun Y et al (2024) A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass. Mol Cell 84:327\u2013344e9","journal-title":"Mol Cell"},{"key":"ref21","article-title":"Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX","volume":"7","author":"Wei L","year":"2024","unstructured":"Wei L et al (2024) Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX. Life Sci Alliance 7","journal-title":"Life Sci Alliance"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1038\/s41467-019-11047-6","article-title":"Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis","volume":"10","author":"Niemi NM","year":"2019","unstructured":"Niemi NM et al (2019) Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis. Nat Commun 10:3197","journal-title":"Nat Commun"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201911659","article-title":"FBXL4 deficiency increases mitochondrial removal by autophagy","author":"Alsina D","year":"2020","unstructured":"Alsina D et al (2020) FBXL4 deficiency increases mitochondrial removal by autophagy. EMBO Mol Med. https:\/\/doi.org\/10.15252\/emmm.201911659","journal-title":"EMBO Mol Med"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen S","year":"2024","unstructured":"Chen S et al (2024) A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625:92\u2013100","journal-title":"Nature"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ymgme.2006.05.015","article-title":"Lactic acidemia and mitochondrial disease","volume":"89","author":"Robinson B","year":"2006","unstructured":"Robinson B (2006) Lactic acidemia and mitochondrial disease. Mol Genet Metab 89:3\u201313","journal-title":"Mol Genet Metab"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.celrep.2015.09.054","article-title":"A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome","volume":"13","author":"Thompson Legault J","year":"2015","unstructured":"Thompson Legault J et al (2015) A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome. Cell Rep 13:981\u2013989","journal-title":"Cell Rep"},{"key":"ref27","doi-asserted-by":"crossref","DOI":"10.1172\/JCI136055","article-title":"Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity","volume":"131","author":"Sharma R","year":"2021","unstructured":"Sharma R et al (2021) Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity. J Clin Invest 131","journal-title":"J Clin Invest"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"105360","DOI":"10.1016\/j.neuint.2022.105360","article-title":"Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain \u03b1-keto acids","volume":"157","author":"Amaral AU","year":"2022","unstructured":"Amaral AU, Wajner M (2022) Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain \u03b1-keto acids. Neurochem Int 157:105360","journal-title":"Neurochem Int"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ymgme.2020.01.006","article-title":"Branched-chain \u03b1-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes","volume":"129","author":"Strauss KA","year":"2020","unstructured":"Strauss KA et al (2020) Branched-chain \u03b1-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Mol Genet Metab 129:193\u2013206","journal-title":"Mol Genet Metab"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.jgg.2015.04.003","article-title":"Genotype\u2013Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update","volume":"42","author":"Caldovic L","year":"2015","unstructured":"Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H (2015) Genotype\u2013Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics 42:181\u2013194","journal-title":"J Genet Genomics"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00374-y","article-title":"Mitochondrial NADP\u2009+\u2009is essential for proline biosynthesis during cell growth","volume":"1\u201315","author":"Tran DH","year":"2021","unstructured":"Tran DH et al (2021) Mitochondrial NADP\u2009+\u2009is essential for proline biosynthesis during cell growth. Nat Metabolism 1\u201315. 10.1038\/s42255-021-00374-y","journal-title":"Nat Metabolism"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"e10575","DOI":"10.7554\/eLife.10575","article-title":"Mitochondrial dysfunction remodels one-carbon metabolism in human cells","volume":"5","author":"Bao XR","year":"2016","unstructured":"Bao XR et al (2016) Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife 5:e10575","journal-title":"eLife"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cmet.2016.01.019","article-title":"Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism","volume":"23","author":"Nikkanen J","year":"2016","unstructured":"Nikkanen J et al (2016) Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism. Cell Metabol 23:635\u2013648","journal-title":"Cell Metabol"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.06.013","article-title":"Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD\u2009+\u2009to alleviate mitochondrial disease","volume":"S1550413121002837","author":"Liu S","year":"2021","unstructured":"Liu S et al (2021) Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD\u2009+\u2009to alleviate mitochondrial disease. Cell Metabol S1550413121002837. 10.1016\/j.cmet.2021.06.013","journal-title":"Cell Metabol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/s41592-020-00999-z","article-title":"Quantitative shotgun proteome analysis by direct infusion","volume":"17","author":"Meyer JG","year":"2020","unstructured":"Meyer JG, Niemi NM, Pagliarini DJ, Coon JJ (2020) Quantitative shotgun proteome analysis by direct infusion. Nat Methods 17:1222\u20131228","journal-title":"Nat Methods"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.molcel.2023.11.038","article-title":"A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass","volume":"84","author":"Sun Y","year":"2024","unstructured":"Sun Y et al (2024) A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass. Mol Cell 84:327\u2013344e9","journal-title":"Mol Cell"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1038\/embor.2013.168","article-title":"Loss of iron triggers PINK1\/Parkin-independent mitophagy","volume":"14","author":"Allen GFG","year":"2013","unstructured":"Allen GFG, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1\/Parkin-independent mitophagy. EMBO Rep 14:1127\u20131135","journal-title":"EMBO Rep"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1042\/BST20221364","article-title":"Coordinating BNIP3\/NIX-mediated mitophagy in space and time","volume":"52","author":"Niemi NM","year":"2024","unstructured":"Niemi NM, Friedman JR (2024) Coordinating BNIP3\/NIX-mediated mitophagy in space and time. Biochem Soc Trans 52:1969\u20131979","journal-title":"Biochem Soc Trans"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1038\/nprot.2017.060","article-title":"A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima","volume":"12","author":"Sun N","year":"2017","unstructured":"Sun N et al (2017) A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat Protoc 12:1576\u20131587","journal-title":"Nat Protoc"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.cell.2009.10.006","article-title":"Serine\/Threonine Phosphatases: Mechanism through Structure","volume":"139","author":"Shi Y","year":"2009","unstructured":"Shi Y (2009) Serine\/Threonine Phosphatases: Mechanism through Structure. Cell 139:468\u2013484","journal-title":"Cell"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"6798","DOI":"10.1002\/j.1460-2075.1996.tb01071.x","article-title":"Crystal structure of the protein serine\/threonine phosphatase 2C at 2.0 A resolution","volume":"15","author":"Das AK","year":"1996","unstructured":"Das AK, Helps NR, Cohen PT, Barford D (1996) Crystal structure of the protein serine\/threonine phosphatase 2C at 2.0 A resolution. EMBO J 15:6798\u20136809","journal-title":"EMBO J"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"20336","DOI":"10.1074\/jbc.274.29.20336","article-title":"Kinetic Analysis of Human Serine\/Threonine Protein Phosphatase 2C\u03b1*","volume":"274","author":"Fjeld CC","year":"1999","unstructured":"Fjeld CC, Denu JM (1999) Kinetic Analysis of Human Serine\/Threonine Protein Phosphatase 2C\u03b1*. J Biol Chem 274:20336\u201320343","journal-title":"J Biol Chem"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/pro.5560050720","article-title":"The protein phosphatase 2C (PP2C) superfamily: Detection of bacterial homologues","volume":"5","author":"Bork P","year":"1996","unstructured":"Bork P, Brown NP, Hegyi H, Schultz J (1996) The protein phosphatase 2C (PP2C) superfamily: Detection of bacterial homologues. Protein Sci 5:1421\u20131425","journal-title":"Protein Sci"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"102784","DOI":"10.1016\/j.ebiom.2020.102784","article-title":"Genetics of mitochondrial diseases: Identifying mutations to help diagnosis","volume":"56","author":"Stenton SL","year":"2020","unstructured":"Stenton SL, Prokisch H (2020) Genetics of mitochondrial diseases: Identifying mutations to help diagnosis. EBioMedicine 56:102784","journal-title":"EBioMedicine"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"4602","DOI":"10.3390\/ijms25094602","article-title":"Digenic Inheritance in Rare Disorders and Mitochondrial Disease\u2014Crossing the Frontier to a More Comprehensive Understanding of Etiology","volume":"25","author":"Neuhofer CM","year":"2024","unstructured":"Neuhofer CM, Prokisch H (2024) Digenic Inheritance in Rare Disorders and Mitochondrial Disease\u2014Crossing the Frontier to a More Comprehensive Understanding of Etiology. Int J Mol Sci 25:4602","journal-title":"Int J Mol Sci"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski KJ","year":"2020","unstructured":"Karczewski KJ et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434\u2013443","journal-title":"Nature"},{"key":"ref47","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2015_491","author":"Antoun G","year":"2016","unstructured":"Antoun G et al (2016) Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion. in JIMD Reports, Volume 27 (eds Morava, E. Springer, Berlin, Heidelberg, 1\u20139 10.1007\/8904_2015_491"},{"key":"ref48","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2019.00039","article-title":"FBXL4-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review","volume":"10","author":"Ballout RA","year":"2019","unstructured":"Ballout RA et al (2019) FBXL4-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review. Front Genet 10","journal-title":"Front Genet"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1111\/cge.12894","article-title":"FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome","volume":"91","author":"Dai H","year":"2017","unstructured":"Dai H et al (2017) FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome. Clin Genet 91:634\u2013639","journal-title":"Clin Genet"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s10545-015-9836-6","article-title":"Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations","volume":"38","author":"Huemer M","year":"2015","unstructured":"Huemer M et al (2015) Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. J Inherit Metab Dis 38:905\u2013914","journal-title":"J Inherit Metab Dis"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1080\/15548627.2023.2274260","article-title":"Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome","volume":"20","author":"Gao K","year":"2024","unstructured":"Gao K, Chen Y, Mo R, Wang C (2024) Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome. Autophagy 20:460\u2013462","journal-title":"Autophagy"},{"key":"ref52","author":"Almannai M","year":"2017","unstructured":"Almannai M, Dai H, El-Hattab A, Wong L (2017) FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome. https:\/\/europepmc.org\/article\/NBK\/nbk425540"},{"key":"ref53","author":"Till A","year":"2012","unstructured":"Till A, Lakhani R, Burnett SF, Subramani S (2012) Pexophagy: The Selective Degradation of Peroxisomes. Int J Cell Biol 512721 (2012)"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"e111115","DOI":"10.15252\/embj.2022111115","article-title":"BNIP3L\/NIX regulates both mitophagy and pexophagy","volume":"41","author":"Wilhelm LP","year":"2022","unstructured":"Wilhelm LP et al (2022) BNIP3L\/NIX regulates both mitophagy and pexophagy. EMBO J 41:e111115","journal-title":"EMBO J"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.celrep.2016.12.049","article-title":"Ptc7p Dephosphorylates Select Mitochondrial Proteins to Enhance Metabolic Function","volume":"18","author":"Guo X","year":"2017","unstructured":"Guo X et al (2017) Ptc7p Dephosphorylates Select Mitochondrial Proteins to Enhance Metabolic Function. Cell Rep 18:307\u2013313","journal-title":"Cell Rep"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"28126","DOI":"10.1074\/jbc.M113.474494","article-title":"The Phosphatase Ptc7 Induces Coenzyme Q Biosynthesis by Activating the Hydroxylase Coq7 in Yeast *","volume":"288","author":"Mart\u00edn-Montalvo A","year":"2013","unstructured":"Mart\u00edn-Montalvo A et al (2013) The Phosphatase Ptc7 Induces Coenzyme Q Biosynthesis by Activating the Hydroxylase Coq7 in Yeast *. J Biol Chem 288:28126\u201328137","journal-title":"J Biol Chem"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.bbabio.2018.09.369","article-title":"The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q10 biosynthesis","volume":"1859","author":"Gonz\u00e1lez-Mariscal I","year":"2018","unstructured":"Gonz\u00e1lez-Mariscal I et al (2018) The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q10 biosynthesis. Biochim et Biophys Acta (BBA) - Bioenergetics 1859:1235\u20131248","journal-title":"Biochim et Biophys Acta (BBA) - Bioenergetics"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"11751","DOI":"10.1074\/jbc.M117.787341","article-title":"Integrative proteomics and biochemical analyses define Ptc6p as the Saccharomyces cerevisiae pyruvate dehydrogenase phosphatase","volume":"292","author":"Guo X","year":"2017","unstructured":"Guo X, Niemi NM, Coon JJ, Pagliarini DJ (2017) Integrative proteomics and biochemical analyses define Ptc6p as the Saccharomyces cerevisiae pyruvate dehydrogenase phosphatase. J Biol Chem 292:11751\u201311759","journal-title":"J Biol Chem"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41582-020-00432-1","article-title":"Hypomyelinating leukodystrophies \u2014 unravelling myelin biology","volume":"17","author":"Wolf NI","year":"2021","unstructured":"Wolf NI, ffrench-Constant C, van der Knaap MS (2021) Hypomyelinating leukodystrophies \u2014 unravelling myelin biology. Nat Rev Neurol 17:88\u2013103","journal-title":"Nat Rev Neurol"},{"key":"ref60","first-page":"1466","article-title":"New Syndrome Characterized by Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum","volume":"23","author":"Knaap MS","year":"2002","unstructured":"van der Knaap MS et al (2002) New Syndrome Characterized by Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum. Am J Neuroradiol 23:1466\u20131474","journal-title":"Am J Neuroradiol"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1055\/s-0036-1584564","article-title":"Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient","volume":"47","author":"Kusk MS","year":"2016","unstructured":"Kusk MS, Damgaard B, Risom L, Hansen B, Ostergaard E (2016) Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient. Neuropediatrics 47:332\u2013335","journal-title":"Neuropediatrics"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ajhg.2008.05.016","article-title":"Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy","volume":"83","author":"Magen D","year":"2008","unstructured":"Magen D et al (2008) Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy. Am J Hum Genet 83:30\u201342","journal-title":"Am J Hum Genet"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/cge.12792","article-title":"Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease","volume":"91","author":"Mierzewska H","year":"2017","unstructured":"Mierzewska H et al (2017) Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease. Clin Genet 91:30\u201337","journal-title":"Clin Genet"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.ajhg.2015.03.003","article-title":"Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination","volume":"96","author":"Nakayama T","year":"2015","unstructured":"Nakayama T et al (2015) Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet 96:709\u2013719","journal-title":"Am J Hum Genet"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"e202302147","DOI":"10.26508\/lsa.202302147","article-title":"Mitochondrial phosphoproteomes are functionally specialized across tissues","volume":"7","author":"Hansen FM","year":"2024","unstructured":"Hansen FM et al (2024) Mitochondrial phosphoproteomes are functionally specialized across tissues. Life Sci Alliance 7:e202302147","journal-title":"Life Sci Alliance"},{"key":"ref66","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2021.100880","article-title":"The extensive and functionally uncharacterized mitochondrial phosphoproteome","volume":"297","author":"Niemi NM","year":"2021","unstructured":"Niemi NM, Pagliarini DJ (2021) The extensive and functionally uncharacterized mitochondrial phosphoproteome. J Biol Chem 297","journal-title":"J Biol Chem"},{"key":"ref67","doi-asserted-by":"crossref","first-page":"19500","DOI":"10.1073\/pnas.0708818104","article-title":"NIX is required for programmed mitochondrial clearance during reticulocyte maturation","volume":"104","author":"Schweers RL","year":"2007","unstructured":"Schweers RL et al (2007) NIX is required for programmed mitochondrial clearance during reticulocyte maturation. PNAS 104:19500\u201319505","journal-title":"PNAS"},{"key":"ref68","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature07006","article-title":"Essential role for Nix in autophagic maturation of erythroid cells","volume":"454","author":"Sandoval H","year":"2008","unstructured":"Sandoval H et al (2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature 454:232\u2013235","journal-title":"Nature"},{"key":"ref69","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01283","article-title":"The Role of Mitophagy in Innate Immunity","volume":"9","author":"Gkikas I","year":"2018","unstructured":"Gkikas I, Palikaras K, Tavernarakis N (2018) The Role of Mitophagy in Innate Immunity. Front Immunol 9","journal-title":"Front Immunol"},{"key":"ref70","author":"Geng G","year":"2021","unstructured":"Geng G et al (2021) Receptor-mediated mitophagy regulates EPO production and protects against renal anemia. eLife 10, e64480"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nri3532","article-title":"Autophagy in infection, inflammation and immunity","volume":"13","author":"Deretic V","year":"2013","unstructured":"Deretic V, Saitoh T, Akira S (2013) Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722\u2013737","journal-title":"Nat Rev Immunol"},{"key":"ref72","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/cge.14632","article-title":"ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder","volume":"107","author":"Almontashiri NAM","year":"2025","unstructured":"Almontashiri NAM et al (2025) ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder. Clin Genet 107:201\u2013207","journal-title":"Clin Genet"},{"key":"ref73","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1083\/jcb.201001083","article-title":"How cyclin A destruction escapes the spindle assembly checkpoint","volume":"190","author":"Fiore B","year":"2010","unstructured":"Di Fiore B, Pines J (2010) How cyclin A destruction escapes the spindle assembly checkpoint. J Cell Biol 190:501\u2013509","journal-title":"J Cell Biol"},{"key":"ref74","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1021\/acs.jproteome.9b00640","article-title":"Skyline for Small Molecules: A Unifying Software Package for Quantitative Metabolomics","volume":"19","author":"Adams KJ","year":"2020","unstructured":"Adams KJ et al (2020) Skyline for Small Molecules: A Unifying Software Package for Quantitative Metabolomics. J Proteome Res 19:1447\u20131458","journal-title":"J Proteome Res"},{"key":"ref75","doi-asserted-by":"crossref","first-page":"5940","DOI":"10.1021\/acs.analchem.7b00396","article-title":"Metabolite Spectral Accuracy on Orbitraps","volume":"89","author":"Su X","year":"2017","unstructured":"Su X, Lu W, Rabinowitz JD (2017) Metabolite Spectral Accuracy on Orbitraps. Anal Chem 89:5940\u20135948","journal-title":"Anal Chem"},{"key":"ref76","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2009\u2013 \u2206\u2206CT Method","volume":"25","author":"Livak KJ","year":"2001","unstructured":"Livak KJ, Schmittgen TD (2001) Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2009\u2013 \u2206\u2206CT Method. Methods 25:402\u2013408","journal-title":"Methods"},{"key":"ref77","doi-asserted-by":"crossref","first-page":"e202507116","DOI":"10.1083\/jcb.202507116","article-title":"Mitochondrial presequences harbor variable strengths to maintain organellar function","volume":"225","author":"Yan Y","year":"2026","unstructured":"Yan Y, Erdenepurev B, Menezes TN, Collinson I, Niemi NM (2026) Mitochondrial presequences harbor variable strengths to maintain organellar function. J Cell Biol 225:e202507116","journal-title":"J Cell Biol"},{"key":"ref78","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: fundamental algorithms for scientific computing in Python","volume":"17","author":"Virtanen P","year":"2020","unstructured":"Virtanen P et al (2020) SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat Methods 17:261\u2013272","journal-title":"Nat Methods"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-8815446\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-8815446\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T14:27:02Z","timestamp":1771511222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-8815446\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":78,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-8815446\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,2,17]]},"subtype":"preprint"}}