Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I
Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who...
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Nature Portfolio
2025-03-01
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| Online Access: | https://doi.org/10.1038/s41598-025-91746-x |
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| author | Veronica Bazzani Deepali L Kundnani Mara Equisoain Redin Francesca Agostini Kirti Chhatlani Angelo Corso Faini Jakub Poziemski Umberto Baccarani Pawel Siedlecki Silvia Deaglio Francesca Storici Carlo Vascotto |
| author_facet | Veronica Bazzani Deepali L Kundnani Mara Equisoain Redin Francesca Agostini Kirti Chhatlani Angelo Corso Faini Jakub Poziemski Umberto Baccarani Pawel Siedlecki Silvia Deaglio Francesca Storici Carlo Vascotto |
| author_sort | Veronica Bazzani |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who underwent liver resection for HCC with no previous pathologies and whose liver showed normal function without signs of cirrhosis. Genetic analysis of mitochondrial DNA (mtDNA) revealed a novel variant of the gene encoding the NADH dehydrogenase subunit 6 (ND6) protein in the tumor tissue. The deletion of a thymidine generated an early stop codon, resulting in a truncated form of the protein (ΔND6) with 50% of the C-terminal primary sequence missing. ND6 is a subunit of the NADH dehydrogenase complex, also known as Complex I, the largest complex in the electron transport chain. Previous studies have linked mtDNA Complex I mutations to mitochondrial disorders and cancer. Through biochemical analyses, we characterized this new mutation and showed that the expression of ΔND6 negatively affects the stability and functionality of Complex I. Data were confirmed by molecular dynamics simulations suggesting conformational rearrangements, overall revealing a leading role of ND6 in the assembly of Complex I. |
| format | Article |
| id | doaj-art-a3bec99af0824558af70d3a00ec3287e |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-a3bec99af0824558af70d3a00ec3287e2025-08-20T02:10:23ZengNature PortfolioScientific Reports2045-23222025-03-0115111110.1038/s41598-025-91746-xCharacterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex IVeronica Bazzani0Deepali L Kundnani1Mara Equisoain Redin2Francesca Agostini3Kirti Chhatlani4Angelo Corso Faini5Jakub Poziemski6Umberto Baccarani7Pawel Siedlecki8Silvia Deaglio9Francesca Storici10Carlo Vascotto11IMol Polish Academy of SciencesSchool of Biological Sciences, Georgia Institute of TechnologyIMol Polish Academy of SciencesDepartment of Medicine, University of UdineSchool of Biological Sciences, Georgia Institute of TechnologyDepartment of Medical Sciences, University of TurinInstitute of Biochemistry and Biophysics, Polish Academy of SciencesDepartment of Medicine, University of UdineInstitute of Biochemistry and Biophysics, Polish Academy of SciencesDepartment of Medical Sciences, University of TurinSchool of Biological Sciences, Georgia Institute of TechnologyIMol Polish Academy of SciencesAbstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who underwent liver resection for HCC with no previous pathologies and whose liver showed normal function without signs of cirrhosis. Genetic analysis of mitochondrial DNA (mtDNA) revealed a novel variant of the gene encoding the NADH dehydrogenase subunit 6 (ND6) protein in the tumor tissue. The deletion of a thymidine generated an early stop codon, resulting in a truncated form of the protein (ΔND6) with 50% of the C-terminal primary sequence missing. ND6 is a subunit of the NADH dehydrogenase complex, also known as Complex I, the largest complex in the electron transport chain. Previous studies have linked mtDNA Complex I mutations to mitochondrial disorders and cancer. Through biochemical analyses, we characterized this new mutation and showed that the expression of ΔND6 negatively affects the stability and functionality of Complex I. Data were confirmed by molecular dynamics simulations suggesting conformational rearrangements, overall revealing a leading role of ND6 in the assembly of Complex I.https://doi.org/10.1038/s41598-025-91746-xHepatocellular carcinomaMitochondriaMitochondrial DNAND6 gene mutationRespiratory complex I assemblyMolecular dynamics simulations. |
| spellingShingle | Veronica Bazzani Deepali L Kundnani Mara Equisoain Redin Francesca Agostini Kirti Chhatlani Angelo Corso Faini Jakub Poziemski Umberto Baccarani Pawel Siedlecki Silvia Deaglio Francesca Storici Carlo Vascotto Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I Scientific Reports Hepatocellular carcinoma Mitochondria Mitochondrial DNA ND6 gene mutation Respiratory complex I assembly Molecular dynamics simulations. |
| title | Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I |
| title_full | Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I |
| title_fullStr | Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I |
| title_full_unstemmed | Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I |
| title_short | Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I |
| title_sort | characterization of a new mutation of mitochondrial nd6 gene in hepatocellular carcinoma and its effects on respiratory complex i |
| topic | Hepatocellular carcinoma Mitochondria Mitochondrial DNA ND6 gene mutation Respiratory complex I assembly Molecular dynamics simulations. |
| url | https://doi.org/10.1038/s41598-025-91746-x |
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