Mitochondria in the biology, pathogenesis, and treatment of hepatitis virus infections

Abstract

Hepatitis virus infections affect a large proportion of the global population. The host responds rapidly to viral infection by orchestrating a variety of cellular machineries, in particular, the mitochondrial compartment. Mitochondria actively regulate viral infections through modulation of the cellular innate immunity and reprogramming of metabolism. In turn, hepatitis viruses are able to modulate the morphodynamics and functions of mitochondria, but the mode of actions are distinct with respect to different types of hepatitis viruses. The resulting mutual interactions between viruses and mitochondria partially explain the clinical presentation of viral hepatitis, influence the response to antiviral treatment, and offer rational avenues for novel therapy. In this review, we aim to consider in depth the multifaceted interactions of mitochondria with hepatitis virus infections and emphasize the implications for understanding pathogenesis and advancing therapeutic development.

Keywords: hepatitis virus; mitochondria; pathogenesis; treatment.

Figure 1

The mutual interactions of the mitochondrial compartment with hepatitis viruses and the consequences on the infections. Hepatitis viruses differentially modulate mitochondria antiviral‐signaling protein (MAVS) signaling. HAV and HCV cleave, while HEV induces MAVS aggregation. These interactions with MAVS result in enhancement or antagonism of innate immune response. Hepatitis viruses either induce or block the mitochondrial permeability transition pore (MPTP) opening, regulating the release of mitochondrial contents such as mitochondrial DNA (mtDNA) fragment or adenosine 5'‐triphosphate (ATP), which then lead to antiviral defense. mtDNA that are not completely degraded are able to enter the endocytic pathway through mitochondria‐derived vesicles, which engage Toll‐like receptor 9 (TLR9) in lysosomes and lead to the activation of the NF‐κB signaling and interferons (IFN) production. Sustained apoptosis caused by hepatitis virus infection triggers damage of membrane integrity, resulting in the liberation of mitochondrial contents into the extracellular milieu

Figure 2

Mitochondrial morphodynamics is differentially regulated by hepatitis viruses to modulate innate immune response. A, The mitochondrial life cycle entails frequent fusion and fission events. Mitofusin‐1 (Mfn1), mitofusin‐2 (Mfn2), and optic atrophy 1 (Opa1) are the key regulators of fusion, whereas dynamin‐related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) modulate fission. HBV and HCV induce fission, whereas HEV triggers fusion. B, Immunofluorescence staining of human liver cells infected with HEV showing the induction of mitochondrial fusion. HEV capsid protein (red; anti‐ORF2), mitochondria (green; anti‐HSP60), and 4',6‐diamidino‐2‐phenylindole DAPI (blue). Cells were visualized with 63× oil immersion lens at identical settings