bims-resufa 2023-05-21 papers

Issue of 2023–05–21
three papers selected by
Vera Strogolova, Strong Microbials, Inc

J Med Virol. 2023 Apr;95(4): e28749

Mitochondrial HIGD1A inhibits hepatitis B virus transcription and replication through the cellular PNKD-NF-κB-NR2F1 nexus.

Zhanglian Xie, Sheng Shen, Kuiyuan Huang, Weibin Wang, Ziying Liu, Haixing Zhang, Mengji Lu, Jian Sun, Jinlin Hou, Hongyan Liu, Haitao Guo, Xiaoyong Zhang.

Hepatitis B Virus (HBV) replication has been reported to be restricted by the intrahepatic host restriction factors and antiviral signaling pathways. The intracellular mechanisms underlying the significant viremia difference among different phases of the natural history chronic HBV infection remain elusive. We herein report that the hypoxia-induced gene domain protein-1a (HIGD1A) was highly expressed in the liver of inactive HBV carriers with low viremia. Ectopic expression of HIGD1A in hepatocyte-derived cells significantly inhibited HBV transcription and replication in a dose-dependent manner, while silence of HIGD1A promoted HBV gene expression and replication. Similar results were also observed in both de novo HBV-infected cell culture model and HBV persistence mouse model. Mechanistically, HIGD1A is located on the mitochondrial inner membrane and activates nuclear factor kappa B (NF-κB) signaling pathway through binding to paroxysmal nonkinesigenic dyskinesia (PNKD), which further enhances the expression of a transcription factor NR2F1 to inhibit HBV transcription and replication. Consistently, knockdown of PNKD or NR2F1 and blockage of NF-κB signaling pathway abrogated the inhibitory effect of HIGD1A on HBV replication. Mitochondrial HIGD1A exploits the PNKD-NF-κB-NR2F1 nexus to act as a host restriction factor of HBV infection. Our study thus shed new lights on the regulation of HBV by hypoxia-related genes and related antiviral strategies.

Keywords: NF-κB; hepatitis B virus (HBV); hypoxia-induced gene domain protein-1a (HIGD1A); nuclear receptor subfamily 2 group F member 1 (NR2F1); paroxysmal nonkinesigenic dyskinesia (PNKD)

DOI: https://doi.org/10.1002/jmv.28749

Nat Commun. 2023 May 15. 14(1): 2783

Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex.

Corey F Hryc, Venkata K P S Mallampalli, Evgeniy I Bovshik, Stavros Azinas, Guizhen Fan, Irina I Serysheva, Genevieve C Sparagna, Matthew L Baker, Eugenia Mileykovskaya, William Dowhan.

Cardiolipin is a hallmark phospholipid of mitochondrial membranes. Despite established significance of cardiolipin in supporting respiratory supercomplex organization, a mechanistic understanding of this lipid-protein interaction is still lacking. To address the essential role of cardiolipin in supercomplex organization, we report cryo-EM structures of a wild type supercomplex (IV1III2IV1) and a supercomplex (III2IV1) isolated from a cardiolipin-lacking Saccharomyces cerevisiae mutant at 3.2-Å and 3.3-Å resolution, respectively, and demonstrate that phosphatidylglycerol in III2IV1 occupies similar positions as cardiolipin in IV1III2IV1. Lipid-protein interactions within these complexes differ, which conceivably underlies the reduced level of IV1III2IV1 and high levels of III2IV1 and free III2 and IV in mutant mitochondria. Here we show that anionic phospholipids interact with positive amino acids and appear to nucleate a phospholipid domain at the interface between the individual complexes, which dampen charge repulsion and further stabilize interaction, respectively, between individual complexes.

DOI: https://doi.org/10.1038/s41467-023-38441-5

Comp Biochem Physiol A Mol Integr Physiol. 2023 May 16. pii: S1095-6433(23)00076-4. [Epub ahead of print] 111443

Hypoxia acclimation improves mitochondrial efficiency in the aerobic swimming muscle of red drum (Sciaenops ocellatus).

Kerri Lynn Ackerly, Benjamin Negrete, Angelina M Dichiera, Andrew J Esbaugh.

Environmental hypoxia (low dissolved oxygen) is a significant threat facing fishes. As fishes require oxygen to efficiently produce ATP, hypoxia can significantly limit aerobic capacity. However, some fishes show respiratory flexibility that rescues aerobic performance, including plasticity in mitochondrial performance. This plasticity may result in increased mitochondrial efficiency (e.g., less proton leak), increased oxygen storage capacity (increased myoglobin), and oxidative capacity (e.g., higher citrate synthase activity) under hypoxia. We acclimated a hypoxia-tolerant fish, red drum (Sciaenops ocellatus), to 8-days of constant hypoxia to induce a hypoxic phenotype. Fish were terminally sampled for cardiac and red muscle tissue to quantify oxidative phosphorylation, proton leak, and maximum respiration in tissue from both hypoxia-acclimated and control fish. Tissue was also collected to assess the plasticity of citrate synthase enzyme activity and mRNA expression for select oxygen storage and antioxidant pathway transcripts. We found that mitochondrial respiration rates were not affected by hypoxia exposure in cardiac tissue, though citrate synthase activity and myoglobin expression were higher following hypoxia acclimation. Interestingly, measures of mitochondrial efficiency in red muscle significantly improved in hypoxia-acclimated individuals. Hypoxia-acclimated fish had significantly higher OXPHOS Control Efficiency, OXPHOS Capacity and Coupling Control Ratios (i.e., LEAK/OXPHOS). There was no significant change to citrate synthase activity or myoglobin expression in red muscle. Overall, these results suggest that red muscle mitochondria of hypoxia-acclimated fish more efficiently utilize oxygen, which may explain previous reports in red drum of improved aerobic swimming performance in the absence of improved maximum metabolic rate following hypoxia acclimation.

Keywords: Fish; Heart; Low oxygen; Oxidative phosphorylation; Red muscle

DOI: https://doi.org/10.1016/j.cbpa.2023.111443