Both the coding and control regions of mitochondrial DNA (mtDNA) play roles in the generation of diabetes; however, no studies have thoroughly reported on the combined diabetogenic effects of variants in the two regions. We determined the mitochondrial haplogroup and the mtDNA sequence of the control region in 859 subjects with diabetes and 1,151 normoglycemic control subjects. Full-length mtDNA sequences were conducted in 40 subjects harboring specific diabetes-related haplogroups. Multivariate logistic regression analysis with adjustment for age, sex, and BMI revealed that subjects harboring the mitochondrial haplogroup B4 have significant association with diabetes (DM) (odds ratio [OR], 1.54 [95% CI 1.18–2.02]; P < 0.001), whereas subjects harboring D4 have borderline resistance against DM generation (0.68 [0.49–0.94]; P = 0.02). Upon further study, we identified an mtDNA composite group susceptible to DM generation consisting of a 10398A allele at the coding region and a polycytosine variant at nucleotide pair 16184–16193 of the control region, as well as a resistant group consisting of C5178A, A10398G, and T152C variants. The OR for susceptible group is 1.31 (95% CI 1.04–1.67; P = 0.024) and for the resistant group is 0.48 (0.31–0.75; P = 0.001). Our study found that mtDNA variants in the coding and control regions can have combined effects influencing diabetes generation.
Background: Increasing evidences have found that the clinical importance of the interaction between hypoxia and immune status in gastric cancer microenvironment. However, reliable prognostic signatures based on combination of hypoxia and immune status have not been well-established. This study aimed to develop a hypoxia-immune-based gene signature for risk stratification in gastric cancer. Methods: Hypoxia and immune status was estimated with transcriptomic profiles for a discovery cohort from GEO database using the t-SNE and ESTIMATE algorithms, respectively. The Cox regression model with the LASSO method was applied to identify prognostic genes and to develop a hypoxia-immune-based gene signature. The TCGA cohort and two independent cohorts from GEO database were used for external validation. Results: Low hypoxia status (p < 0.001) and high immune status (p = 0.005) were identified as favorable factors for patients' overall survival. By using the LASSO model, four genes, including CXCR6, PPP1R14A and TAGLN, were identified to construct a gene signature for risk stratification. In the discovery cohort (n = 357), patients with low risk yielded better outcomes than those with high risk regarding overall survival across and within TNM stage subgroups. Multivariate analysis identified the hypoxia-immune-based gene signature as an independent prognostic factor (p < 0.001). A nomogram integrating the gene signature and known risk factors yielded better performance and net benefits in calibration and decision curve analyses. Similar results were validated in the TCGA (n = 321) and two independent GEO (n = 300 and n = 136, respectively) cohorts. Conclusions: The hypoxia-immune-based gene signature represents a promising tool for risk stratification tool in gastric cancer. It might serve as a prognostic classifier for clinical decision-making regarding individualized prognostication and treatment, and follow-up scheduling.
Background Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D-susceptible haplogroup B4 remains unanswered. Methods To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS-AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi-1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. Results Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1-AKT pathway and GLUT translocation stimulated by insulin were improved. On the contrary, suppression of mitochondrial network caused a reduction of the IRS1-AKT pathway and GLUT translocation stimulated by insulin. Pharmacologically inhibiting mitochondrial fission by the Drp1 inhibitor, mdivi-1, also rescued mitochondrial network, reduced mtROS, and improved insulin signaling of diabetes-susceptible cybrid cells. Conclusion Our results discovered the causal role of mtDYN proteins in regulating IR resulted from diabetes-susceptible mitochondrial haplogroup. The existence of a bidirectional interaction between mtDYN and mtROS plays an important role. Direct intervention to reverse profission in mtDYN provides a novel therapeutic strategy for IR and T2D.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.