PDF(Pubmed)
Abstract：
Alcoholic liver disease (ALD) poses a substantial global health challenge, with its pathogenesis deeply rooted in mitochondrial dysfunction. Our study explores the pivotal roles of Phosphoglycerate mutase family member 5 (Pgam5) and Voltage-Dependent Anion Channel 1 (VDAC1) in the progression of ALD, providing novel insights into their interplay and impact on mitochondrial integrity. We demonstrate that Pgam5 silencing preserves hepatocyte viability and attenuates ethanol-induced apoptosis, underscoring its detrimental role in exacerbating hepatocyte dysfunction. Pgam5\'s influence extends to the regulation of VDAC1 oligomerization, a key process in mitochondrial permeability transition pore (mPTP) opening, mitochondrial swelling, and apoptosis initiation. Notably, the inhibition of VDAC1 oligomerization through Pgam5 silencing or pharmacological intervention (VBIT-12) significantly preserves mitochondrial function, evident in the maintenance of mitochondrial membrane potential and reduced reactive oxygen species (ROS) production. In vivo experiments using hepatocyte-specific Pgam5 knockout (Pgam5hKO) and control mice reveal that Pgam5 deficiency mitigates ethanol-induced liver histopathology, inflammation, lipid peroxidation, and metabolic disorder, further supporting its role in ALD progression. Our findings highlight the critical involvement of Pgam5 and VDAC1 in mitochondrial dysfunction in ALD, suggesting potential therapeutic targets. While promising, these findings necessitate further research, including human studies, to validate their clinical applicability and explore broader implications in liver diseases. Overall, our study provides a significant advancement in understanding ALD pathophysiology, paving the way for novel therapeutic strategies targeting mitochondrial pathways in ALD.
摘要：
酒精性肝病（ALD）构成了巨大的全球健康挑战，其发病机制深深植根于线粒体功能障碍。我们的研究探讨了磷酸甘油酸变位酶家族成员5（Pgam5）和电压依赖性阴离子通道1（VDAC1）在ALD进展中的关键作用，为它们的相互作用和对线粒体完整性的影响提供新的见解。我们证明Pgam5沉默保留肝细胞活力并减弱乙醇诱导的细胞凋亡，强调其在加剧肝细胞功能障碍中的有害作用。Pgam5的影响延伸到VDAC1寡聚化的调节，线粒体通透性转换孔（mPTP）开放的关键过程，线粒体肿胀,和凋亡起始。值得注意的是,通过Pgam5沉默或药物干预（VBIT-12）抑制VDAC1寡聚化显著保留线粒体功能，在维持线粒体膜电位和减少活性氧（ROS）产生方面很明显。使用肝细胞特异性Pgam5敲除（Pgam5hKO）和对照小鼠的体内实验表明，Pgam5缺乏减轻乙醇诱导的肝组织病理学，炎症,脂质过氧化，和代谢紊乱，进一步支持其在ALD进展中的作用。我们的发现强调了Pgam5和VDAC1在ALD线粒体功能障碍中的关键参与，提示潜在的治疗靶点。虽然有希望，这些发现需要进一步的研究，包括人类研究,以验证其临床适用性并探索在肝脏疾病中更广泛的意义。总的来说,我们的研究为理解ALD病理生理学提供了重大进展，为ALD中针对线粒体途径的新型治疗策略铺平了道路。
