Respiration defects limit serine synthesis required for lung cancer growth and survival
Abstract Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show...
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| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62911-7 |
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| author | Eduardo Cararo Lopes Fuqian Shi Akshada Sawant Maria Ibrahim Maria Gomez-Jenkins Zhixian Hu Pranav Manchiraju Vrushank Bhatt Wenping Wang Christian S. Hinrichs Douglas C. Wallace Xiaoyang Su Joshua D. Rabinowitz Chang S. Chan Jessie Yanxiang Guo Shridar Ganesan Edmund C. Lattime Eileen White |
| author_facet | Eduardo Cararo Lopes Fuqian Shi Akshada Sawant Maria Ibrahim Maria Gomez-Jenkins Zhixian Hu Pranav Manchiraju Vrushank Bhatt Wenping Wang Christian S. Hinrichs Douglas C. Wallace Xiaoyang Su Joshua D. Rabinowitz Chang S. Chan Jessie Yanxiang Guo Shridar Ganesan Edmund C. Lattime Eileen White |
| author_sort | Eduardo Cararo Lopes |
| collection | DOAJ |
| description | Abstract Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA. |
| format | Article |
| id | doaj-art-ccabe562ba9f477fb4eeea28af96b3db |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ccabe562ba9f477fb4eeea28af96b3db2025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-08-0116111710.1038/s41467-025-62911-7Respiration defects limit serine synthesis required for lung cancer growth and survivalEduardo Cararo Lopes0Fuqian Shi1Akshada Sawant2Maria Ibrahim3Maria Gomez-Jenkins4Zhixian Hu5Pranav Manchiraju6Vrushank Bhatt7Wenping Wang8Christian S. Hinrichs9Douglas C. Wallace10Xiaoyang Su11Joshua D. Rabinowitz12Chang S. Chan13Jessie Yanxiang Guo14Shridar Ganesan15Edmund C. Lattime16Eileen White17Rutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteCenter for Mitochondrial and Epigenomic Medicine, the Children’s Hospital of Philadelphia and Department of Pediatrics, Division of Human Genetics, The Perelman School of Medicine, University of PennsylvaniaRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteRutgers Cancer InstituteAbstract Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA.https://doi.org/10.1038/s41467-025-62911-7 |
| spellingShingle | Eduardo Cararo Lopes Fuqian Shi Akshada Sawant Maria Ibrahim Maria Gomez-Jenkins Zhixian Hu Pranav Manchiraju Vrushank Bhatt Wenping Wang Christian S. Hinrichs Douglas C. Wallace Xiaoyang Su Joshua D. Rabinowitz Chang S. Chan Jessie Yanxiang Guo Shridar Ganesan Edmund C. Lattime Eileen White Respiration defects limit serine synthesis required for lung cancer growth and survival Nature Communications |
| title | Respiration defects limit serine synthesis required for lung cancer growth and survival |
| title_full | Respiration defects limit serine synthesis required for lung cancer growth and survival |
| title_fullStr | Respiration defects limit serine synthesis required for lung cancer growth and survival |
| title_full_unstemmed | Respiration defects limit serine synthesis required for lung cancer growth and survival |
| title_short | Respiration defects limit serine synthesis required for lung cancer growth and survival |
| title_sort | respiration defects limit serine synthesis required for lung cancer growth and survival |
| url | https://doi.org/10.1038/s41467-025-62911-7 |
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