Figures
Figure 1
Morphologic alterations of mitochondria by flaviviruses and HCV. Left panel: schematicrepresentation of mitochondrial fusion caused by flaviviruses through the phosphorylation inhibition of dynamin-related protein 1 (DRP1) fission factor. Convoluted membranes (CM) enriched in NS3, NS4B and NS4A flaviviral proteins are connected to mitochondria via a residual endoplasmic reticulum (ER) tubule while ER-mitochondria contacts (ERMC) are altered. Middle panel: Schematicrepresentation of the fusion/fission equilibrium in uninfected conditions. Right panel: Schematicrepresentation of mitochondrial fission induced by HCV. The virus favors DRP1 translocation to mitochondria.
This figure was drawn with the help of the BioRender online software (https://biorender.com/ ).
Figure 1
Figure 2
Impact of flavivirus and HCV infection on mitochondrial metabolism. Left panel: schematicrepresentation of mitochondrial metabolism perturbations by flaviviruses. Viral proteins cause lipid droplet (LD) lipophagy and fatty acid synthesis by the fatty acid synthase (FASN) leading to the increase of β-oxidation and mitochondrial respiration. Middle panel: schematic representation of mitochondrial metabolism in uninfected conditions. Right panel: schematic representation of downregulated mitochondrial respiration by HCV.
MTP: mitochondrial trifunctional protein; AUP1: ancient ubiquitous protein 1; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin.
This figure was drawn with the help of the BioRender online software (https://biorender.com/ ).
Figure 2
Figure 3
Subversion of innate immunity by flaviviruses and HCV. Left panel: schematic representation of interference mechanisms in early innate immune signaling pathways by flaviviruses. Middle panel: schematic representation of early innate immune signaling pathways in classical RNA virus infection. The viral RNA is recognized by retinoic acid-inducible gene I (RIG-I) without interference mechanisms. The indirect impact of infection on the interferon (IFN) pathway through the release of mitochondrial DNA (mtDNA) from mitochondria and its recognition via cyclic GMP-AMP synthase (cGAS) is also illustrated. Right panel: schematic representation of the downregulation of early innate immunity by HCV.
Scissors: proteolytic cleavage; MAVS: mitochondrial antiviral-signaling protein; STING: stimulator of interferon genes protein; TRIM25: tripartite motif-containing protein 25; TBK1: TANK-binding kinase 1; IKKɛ: inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF3, 7: interferon regulatory factor 3 and 7; sfRNA: subgenomic flaviviral RNA; Ub: ubiquitin; CM: convoluted membranes; ERMC: ER-mitochondria contacts; ER: endoplasmic reticulum.
This figure was drawn with the help of the BioRender online software (https://biorender.com/ ).
Figure 3
Figure 4
Apoptosis perturbations by flaviviruses and HCV. Left panel: schematic representation of up- or downregulation of apoptosis induction by flaviviruses. Middle panel : schematic representation of the intrinsic apoptosis pathway in uninfected conditions. Right panel: schematic representation of apoptosis downregulation by HCV.
CM: convoluted membranes; ER: endoplasmic reticulum; PI3K: phosphatidylinositol 3-kinase; sfRNA: subgenomic flaviviral RNA; VCP: valosin-containing protein.
This figure was drawn with the help of the BioRender online software (https://biorender.com/ ).
Figure 4
Authors
Centre Armand-Frappier
santé biotechnologie,
Institut national
de la recherche scientifique,
Laval, Québec, Canada
Infections with Flaviviridae constitute a major public health concern, especially considering the limited availability of prophylactic and therapeutic treatments. Most notably, the recent emergence of Zika virus in the Americas was associated with the dramatic increase of severe symptoms such as congenital microcephaly, while hepatitis C virus causes the death of approximately 300,000 individuals annually. Flaviviridae have evolved to hijack cellular organelles and to favor their replication, often via divergent molecular mechanisms. In addition to the remodeling of the endoplasmic reticulum, which is required for the replication of the viral genome and the assembly of the neosynthesized virions, Flaviviridae induce drastic morphological alterations of the mitochondria. This is associated with the viral co-opting of several key mitochondrial functions in apoptosis, innate immunity and metabolism. This review recapitulates the current knowledge about the morphological and functional relationship between Flaviviridae and mitochondria and explains how this contributes to the establishment of a cytoplasmic environment which is favorable to viral replication.