Mitophagy in Antiviral Immunity

Abstract

Mitochondria are important organelles whose primary function is energy production; in addition, they serve as signaling platforms for apoptosis and antiviral immunity. The central role of mitochondria in oxidative phosphorylation and apoptosis requires their quality to be tightly regulated. Mitophagy is the main cellular process responsible for mitochondrial quality control. It selectively sends damaged or excess mitochondria to the lysosomes for degradation and plays a critical role in maintaining cellular homeostasis. However, increasing evidence shows that viruses utilize mitophagy to promote their survival. Viruses use various strategies to manipulate mitophagy to eliminate critical, mitochondria-localized immune molecules in order to escape host immune attacks. In this article, we will review the scientific advances in mitophagy in viral infections and summarize how the host immune system responds to viral infection and how viruses manipulate host mitophagy to evade the host immune system.

Keywords: autophagy; immune; infection; mitochondria; mitophagy; virus.

FIGURE 1

Mitochondrial dynamics and the molecular mechanism of mitophagy. In the physiological state, mitochondria fuse to form a tubular structure via the action of MFN1 and MFN2. In the pathological state, mitochondria are damaged and split into smaller granular mitochondria via the action of Drp1. The damaged mitochondria are degraded through either ubiquitin-dependent or ubiquitin-independent mitophagy. During ubiquitin-dependent mitophagy, PINK1 accumulates on the mitochondrial outer membrane, recruiting and activating the E3 ligase Parkin. Parkin ubiquitinates mitochondrial outer membrane proteins, including MFN1 and MFN2. The mitophagy adapter proteins p62, NDP52, and optineurin connect LC3 to ubiquitinated proteins on the OMM and guide mitochondria into the phagophore. In ubiquitin-independent mitophagy, mitophagy OMM receptors such as NIX, BNIP3, FUNDC1, BCL2L13, FKBP8, and IMM receptor PHB2, as well as mitochondrial lipids, including cardiolipin and ceramide, interact with LC3 directly. The phagophore gradually expands to form a double-layered autophagosome. Autophagosomes and lysosome fuse to form a single-layer-membrane-wrapped autolysosome to degrade and recycle the damaged mitochondrial substances.

FIGURE 2

The mechanism of viral-induced mitophagy. Following viral infection, the GTPase Drp1 wraps around certain sites of mitochondria, forcing them to divide. This causes the mitochondria to separate from the tubular structure. Some viruses such as HBV and HCV utilize ubiquitin-dependent mitophagy. They upregulate the expression of PINK1 and Parkin, leading to the aggregation of PINK1 on the OMM, recruitment of the E3 ligase Parkin, and Parkin activation via phosphorylation. Activated Parkin can ubiquitinate OMM proteins such as MFN1 and MFN2. The poly-ubiquitinated OMM proteins serve as binding sites for both mitophagy adaptors (optineurin, p62, and NDP52) and LC3. The mitochondria can then be wrapped around by autophagosome and degraded by autophagy. Other viruses, such as IAV, HPIV3, and HTNV, can induce mitophagy via interactions with both LC3 and the mitochondrial elongation factor, TUFM. Interestingly, the HHV-8-encoded viral protein vIRF-1 directly induces NIX-mediated mitophagy in host cells.

FIGURE 3

The effect of virus-induced mitophagy on the host immune system. Upon viral infection, RLRs (including MDA5 and RIG-I) on the host cell surface sense viral RNA and induce MAVS to form prion-like aggregates, which further trigger type I IFN production. Virus-induced mitophagy leads to the degradation of MAVS, thereby weakening the type I IFN response of the host. Furthermore, virus-induced mitophagy also removes damaged mitochondria to inhibit the activation of cGAS-STING signaling pathways and the inflammasome; ER, endoplasmic reticulum; mROS, mitochondrial ROS.