Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification

作者：Zhiqiang Wei, Yanying Yan, Lingzhu Zhao, Chen Li, Jinjin Qi, Dandan Chen, Xiuzhen Huang, Minwei Li, Zhengyun Xiao, Guohua Lou, Zhenggang Yang, Mengji Lu, Xueyu Wang, Min Zheng · 发表于：Emerging Microbes & Infections · 年份：2025 · DOI：10.1080/22221751.2025.2563079 · 被引用次数：7 · 研究领域：Autophagy in Disease and Therapy、Neonatal Health and Biochemistry、Heme Oxygenase-1 and Carbon Monoxide

Mitochondria are vital for maintaining cellular homeostasis. However, mitochondrial damage is evident in patients with chronic hepatitis B (CHB). The role of mitochondrial dysfunction in the persistence of viral replication remains unclear. Therefore, this study aims to investigate the impact of mitochondrial dysfunction on HBV replication and elucidate the underlying mechanisms. Both mitochondria and lysosomes were dysfunctional in HBV-replicating cells. Moreover, HBV replication inhibited mitochondrial respiratory chain both in vitro and in vivo. Moderate inhibition of mitochondrial respiratory complex I activity using rotenone (Rot) increased HBV replication and decreased autophagic degradation capacity in vitro and in vivo. Mechanistically, elevated mitochondrial reactive oxygen species (mtROS) levels by Rot treatment or SOD2 knockdown led to deteriorated lysosomal membrane permeabilization, which elevated lysosomal pH and promoted HBV replication. Conversely, scavenging mtROS with mitoquinone (mitoQ) and mitoTEMPO (mitoT) had the opposite effect. Additionally, mitochondrial dysfunction reduced mitochondrial ATP production and diminished mitochondria-lysosome contacts. Obstructing mitochondrial ATP synthesis with Oligomycin A treatment or disruption of mitochondria-lysosome contacts with vacuolar protein sorting 13 A (VPS13A) knockdown resulted in lysosomal alkalinization and increased HBV replication by inhibiting vacuolar (H+)-adenosine triphosphatase (v-ATPase) assembl...