Dataset Information

Mitochondrial Dynamics Related Genes -MFN1, MFN2 and DRP1 Polymorphisms are Associated with Risk of Lung Cancer.

ABSTRACT:

Purpose

This study aimed to evaluate the associations between mitochondrial dynamics related genes -MFN1, MFN2 and DRP1 polymorphisms and risk of lung cancer.

Methods

Six polymorphisms of MFN1, MFN2 and DRP1 were genotyped in 600 cases and 600 controls using a MassARRAY platform.

Results

The MFN1 rs13098637-C and DRP1 rs879255689-A alleles were associated with an increased risk of lung cancer (p _rs13098637=0.004, p _rs879255689=0.005), while MFN2 rs4240897-A and rs2236058-G were related to a decreased risk of disease (p<0.001). The rs13098637-TC/CC and rs879255689-GA/AA were determined as risk genotypes for lung cancer (p _rs13098637=0.014, p _rs879255689=0.013), whereas the rs4240897-GA/AA and rs2236058-GG were identified as protective genotypes against lung cancer risk (p<0.001). Genetic model analysis showed that rs13098637 was correlated with an elevated risk of lung cancer in dominant and log-additive models (p _dominant=0.007, p _log-additive=0.004). Moreover, rs879255689 was associated with an increased risk of disease in all three models (p _dominant=0.014, p _recessive=0.028, p _log-additive=0.005). In contrast, rs4240897 and rs2236058 were related to reduced risk of disease in all three models (rs4240897: p _all<0.001; rs2236058: p _dominant=0.008, p _recessive<0.001, p _log-additive<0.001). In addition, these associations were related to the smoking status and pathological type of lung cancer patients.

Conclusion

These results shed new light on the association between mitochondrial dynamics related genes and risk of lung cancer.

SUBMITTER: Liang X

PROVIDER: S-EPMC8214204 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering.