The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study.

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.