Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University, Rome, Italy.
IRCCS Neuromed, Pozzilli (Is), Italy.
Mol Med. 2023 Aug 9;29(1):107. doi: 10.1186/s10020-023-00701-x.
A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes.
Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway.
The TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway.
We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.
先前的实验研究表明，NADH 脱氢酶（线粒体复合物 I，CI）功能障碍与左心室肥厚（LVH）的发展有关。Ndufc2（CI 的亚单位）的缺乏会损害 CI 活性，导致严重的线粒体功能障碍。NDUFC2/rs11237379 变体的 T 等位基因与基因表达减少和线粒体功能受损有关。本研究检测了 NDUFC2/rs11237379 和 NDUFC2/rs641836 变体与高血压患者 LVH 的关联。体外研究探讨了在分离的心肌细胞中降低 Ndufc2 表达的影响。
纳入 246 名受试者（男性 147 名，占 59.7%），平均年龄为 59±15 岁，进行基因关联分析。在 H9c2 和大鼠原代心肌细胞中进行 Ndufc2 沉默，以探讨心肌肥厚的发展及其潜在的信号通路。
NDUFC2/rs11237379 处的 TT 基因型与基因表达显著降低相关。多变量分析显示，携带该基因型的患者室间隔厚度（p=0.07）、后壁厚度（p=0.008）、RWT（p=0.021）、LV 质量/BSA（p=0.03）与携带 CC 或 CT 基因型的患者相比存在显著差异。携带 NDUFC2/rs641836 的 A 等位基因的患者室间隔厚度（p=0.017）、后壁厚度（p=0.011）、LV 质量（p=0.003）、LV 质量/BSA（p=0.002）和 LV 质量/身高（p=0.010）在调整协变量后存在显著差异。在体外，Ndufc2 缺乏依赖性的线粒体功能障碍导致心肌细胞肥大，表明 SIRT3-AMPK-AKT-MnSOD 是主要的潜在信号通路。
我们首次证明 NDUFC2 变体与人类高血压中的 LVH 显著相关，并强调 Ndufc2 缺乏依赖性 CI 线粒体功能障碍在增加心脏肥大发展的易感性方面起着关键作用。
