The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study
Abstract Background Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-re...
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2025-04-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-025-14201-0 |
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| author | Jincheng Tang Jingting Zhang Renyi Yang Hongyao Chen Xiaopeng Yu Wei Peng Puhua Zeng |
| author_facet | Jincheng Tang Jingting Zhang Renyi Yang Hongyao Chen Xiaopeng Yu Wei Peng Puhua Zeng |
| author_sort | Jincheng Tang |
| collection | DOAJ |
| description | Abstract Background Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-related exposures on six major cancers—hepatic, colorectal, lung, esophageal, thyroid, and breast—using Mendelian randomization (MR). Methods Two-sample MR analysis was performed using the inverse variance weighted (IVW) method, with MR-Egger regression and weighted median as complementary approaches. Sensitivity analyses (Cochran’s Q test, MR-Egger intercept, leave-one-out) and the Steiger test were applied to assess heterogeneity, pleiotropy, and causal directionality. Results We observed a negative correlation between “39S ribosomal protein L34, mitochondrial”, and others, with hepatic cancer, while “[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial”, and others exhibited a positive correlation with hepatic cancer. “Phenylalanine-tRNA ligase, mitochondrial”, and others demonstrated a negative association with colorectal cancer, whereas “Methylmalonyl-CoA epimerase, mitochondrial”, and others exhibited a positive correlation with colorectal cancer. “Succinate dehydrogenase assembly factor 2, mitochondrial” exhibited a negative correlation with lung cancer, while “Superoxide dismutase [Mn], mitochondrial levels” showed a positive correlation with lung cancer. “Lon protease homolog, mitochondrial” demonstrated a positive correlation with esophageal cancer. “Iron-sulfur cluster assembly enzyme ISCU, mitochondrial”, and others exhibited a negative correlation with thyroid cancer, while “Diablo homolog, mitochondrial”, and others showed a positive correlation with thyroid cancer. “ADP-ribose pyrophosphatase, mitochondrial”, and others exhibited a negative correlation with breast cancer, while “39S ribosomal protein L34, mitochondrial”, and others showed a positive correlation with breast cancer. Conclusions This study provides MR-based evidence that specific mitochondrial-related traits have causal effects on the risk of several common cancers. Notably, certain single-nucleotide polymorphisms (SNPs) acted as instrumental variables across multiple cancer types through shared mitochondrial mechanisms, such as oxidative stress regulation and metabolic reprogramming. These findings highlight mitochondria as cross-cutting contributors to cancer susceptibility and suggest potential avenues for mitochondrial-targeted prevention and therapy. The identification of pleiotropic genetic variants also offers insights for developing shared biomarkers and therapeutic targets across malignancies. |
| format | Article |
| id | doaj-art-b3348ad5d47642b08d91c363c4d0b276 |
| institution | DOAJ |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj-art-b3348ad5d47642b08d91c363c4d0b2762025-08-20T02:55:38ZengBMCBMC Cancer1471-24072025-04-0125111310.1186/s12885-025-14201-0The causal relationships between mitochondria and six types of cancer: a Mendelian randomization studyJincheng Tang0Jingting Zhang1Renyi Yang2Hongyao Chen3Xiaopeng Yu4Wei Peng5Puhua Zeng6Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese MedicineHunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese MedicineHunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese MedicineHunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese MedicineHunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese MedicineCancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese MedicineCancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese MedicineAbstract Background Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-related exposures on six major cancers—hepatic, colorectal, lung, esophageal, thyroid, and breast—using Mendelian randomization (MR). Methods Two-sample MR analysis was performed using the inverse variance weighted (IVW) method, with MR-Egger regression and weighted median as complementary approaches. Sensitivity analyses (Cochran’s Q test, MR-Egger intercept, leave-one-out) and the Steiger test were applied to assess heterogeneity, pleiotropy, and causal directionality. Results We observed a negative correlation between “39S ribosomal protein L34, mitochondrial”, and others, with hepatic cancer, while “[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial”, and others exhibited a positive correlation with hepatic cancer. “Phenylalanine-tRNA ligase, mitochondrial”, and others demonstrated a negative association with colorectal cancer, whereas “Methylmalonyl-CoA epimerase, mitochondrial”, and others exhibited a positive correlation with colorectal cancer. “Succinate dehydrogenase assembly factor 2, mitochondrial” exhibited a negative correlation with lung cancer, while “Superoxide dismutase [Mn], mitochondrial levels” showed a positive correlation with lung cancer. “Lon protease homolog, mitochondrial” demonstrated a positive correlation with esophageal cancer. “Iron-sulfur cluster assembly enzyme ISCU, mitochondrial”, and others exhibited a negative correlation with thyroid cancer, while “Diablo homolog, mitochondrial”, and others showed a positive correlation with thyroid cancer. “ADP-ribose pyrophosphatase, mitochondrial”, and others exhibited a negative correlation with breast cancer, while “39S ribosomal protein L34, mitochondrial”, and others showed a positive correlation with breast cancer. Conclusions This study provides MR-based evidence that specific mitochondrial-related traits have causal effects on the risk of several common cancers. Notably, certain single-nucleotide polymorphisms (SNPs) acted as instrumental variables across multiple cancer types through shared mitochondrial mechanisms, such as oxidative stress regulation and metabolic reprogramming. These findings highlight mitochondria as cross-cutting contributors to cancer susceptibility and suggest potential avenues for mitochondrial-targeted prevention and therapy. The identification of pleiotropic genetic variants also offers insights for developing shared biomarkers and therapeutic targets across malignancies.https://doi.org/10.1186/s12885-025-14201-0Mendelian randomizationMitochondriaCancersCausal inference |
| spellingShingle | Jincheng Tang Jingting Zhang Renyi Yang Hongyao Chen Xiaopeng Yu Wei Peng Puhua Zeng The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study BMC Cancer Mendelian randomization Mitochondria Cancers Causal inference |
| title | The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study |
| title_full | The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study |
| title_fullStr | The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study |
| title_full_unstemmed | The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study |
| title_short | The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study |
| title_sort | causal relationships between mitochondria and six types of cancer a mendelian randomization study |
| topic | Mendelian randomization Mitochondria Cancers Causal inference |
| url | https://doi.org/10.1186/s12885-025-14201-0 |
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