{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:33:20Z","timestamp":1788431600425,"version":"build-2803163510"},"reference-count":100,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T00:00:00Z","timestamp":1719619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 67084"],"award-info":[{"award-number":["MOP 67084"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1\u03b1 and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1\/HK2, ALDOA, ENO2, PKM, LDHA\/LDHB, MCT4, PDHA1, PDK1\/3, MPC1\/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1\u03b1, a transcriptional coactivator for transcription factors PPAR\u03b1, ERR\u03b1, and ERR\u03b3, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms25137173","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4130-4136","authenticated-orcid":false,"given":"Xuewen","family":"Song","sequence":"first","affiliation":[{"name":"Division of Nephrology, University Health Network, Toronto, ON M5G 2N2, Canada"},{"name":"Department of Medicine, Division of Nephrology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6025-0915","authenticated-orcid":false,"given":"Lauren","family":"Pickel","sequence":"additional","affiliation":[{"name":"Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6677-9385","authenticated-orcid":false,"given":"Hoon-Ki","family":"Sung","sequence":"additional","affiliation":[{"name":"Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Scholey","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University Health Network, Toronto, ON M5G 2N2, Canada"},{"name":"Department of Medicine, Division of Nephrology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"York","family":"Pei","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University Health Network, Toronto, ON M5G 2N2, Canada"},{"name":"Department of Medicine, Division of Nephrology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1681\/ASN.2018050493","article-title":"Prevalence estimates of polycystic kidney and liver disease by population sequencing","volume":"29","author":"Lanktree","year":"2018","journal-title":"J. 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