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Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate the...

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Autores principales: Marchese, Emanuela, Caterino, Marianna, Fedele, Roberta, Pirozzi, Francesca, Cevenini, Armando, Gupta, Neha, Ingrosso, Diego, Perna, Alessandra, Capasso, Giovambattista, Ruoppolo, Margherita, Zacchia, Miriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409368/
https://www.ncbi.nlm.nih.gov/pubmed/36012682
http://dx.doi.org/10.3390/ijms23169420
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author Marchese, Emanuela
Caterino, Marianna
Fedele, Roberta
Pirozzi, Francesca
Cevenini, Armando
Gupta, Neha
Ingrosso, Diego
Perna, Alessandra
Capasso, Giovambattista
Ruoppolo, Margherita
Zacchia, Miriam
author_facet Marchese, Emanuela
Caterino, Marianna
Fedele, Roberta
Pirozzi, Francesca
Cevenini, Armando
Gupta, Neha
Ingrosso, Diego
Perna, Alessandra
Capasso, Giovambattista
Ruoppolo, Margherita
Zacchia, Miriam
author_sort Marchese, Emanuela
collection PubMed
description Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.
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spelling pubmed-94093682022-08-26 Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome Marchese, Emanuela Caterino, Marianna Fedele, Roberta Pirozzi, Francesca Cevenini, Armando Gupta, Neha Ingrosso, Diego Perna, Alessandra Capasso, Giovambattista Ruoppolo, Margherita Zacchia, Miriam Int J Mol Sci Article Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism. MDPI 2022-08-20 /pmc/articles/PMC9409368/ /pubmed/36012682 http://dx.doi.org/10.3390/ijms23169420 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marchese, Emanuela
Caterino, Marianna
Fedele, Roberta
Pirozzi, Francesca
Cevenini, Armando
Gupta, Neha
Ingrosso, Diego
Perna, Alessandra
Capasso, Giovambattista
Ruoppolo, Margherita
Zacchia, Miriam
Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title_full Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title_fullStr Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title_full_unstemmed Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title_short Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
title_sort multi-omics studies unveil extraciliary functions of bbs10 and show metabolic aberrations underlying renal disease in bardet–biedl syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409368/
https://www.ncbi.nlm.nih.gov/pubmed/36012682
http://dx.doi.org/10.3390/ijms23169420
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