Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria
Abstract Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38027-1 |
| _version_ | 1797836356032921600 |
|---|---|
| author | Janne Purhonen Rishi Banerjee Vilma Wanne Nina Sipari Matthias Mörgelin Vineta Fellman Jukka Kallijärvi |
| author_facet | Janne Purhonen Rishi Banerjee Vilma Wanne Nina Sipari Matthias Mörgelin Vineta Fellman Jukka Kallijärvi |
| author_sort | Janne Purhonen |
| collection | DOAJ |
| description | Abstract Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases. |
| first_indexed | 2024-04-09T15:08:35Z |
| format | Article |
| id | doaj.art-72543377fa1045cd9ce8e1279a29add7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T15:08:35Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-72543377fa1045cd9ce8e1279a29add72023-04-30T11:21:53ZengNature PortfolioNature Communications2041-17232023-04-0114112310.1038/s41467-023-38027-1Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeriaJanne Purhonen0Rishi Banerjee1Vilma Wanne2Nina Sipari3Matthias Mörgelin4Vineta Fellman5Jukka Kallijärvi6Folkhälsan Research CenterFolkhälsan Research CenterFolkhälsan Research CenterViikki Metabolomics Unit, University of HelsinkiDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityFolkhälsan Research CenterFolkhälsan Research CenterAbstract Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.https://doi.org/10.1038/s41467-023-38027-1 |
| spellingShingle | Janne Purhonen Rishi Banerjee Vilma Wanne Nina Sipari Matthias Mörgelin Vineta Fellman Jukka Kallijärvi Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria Nature Communications |
| title | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| title_full | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| title_fullStr | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| title_full_unstemmed | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| title_short | Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| title_sort | mitochondrial complex iii deficiency drives c myc overexpression and illicit cell cycle entry leading to senescence and segmental progeria |
| url | https://doi.org/10.1038/s41467-023-38027-1 |
| work_keys_str_mv | AT jannepurhonen mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT rishibanerjee mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT vilmawanne mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT ninasipari mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT matthiasmorgelin mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT vinetafellman mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria AT jukkakallijarvi mitochondrialcomplexiiideficiencydrivescmycoverexpressionandillicitcellcycleentryleadingtosenescenceandsegmentalprogeria |