Abstract
Mitochondrial dynamics is essential for the maintenance of cell homeostasis. Previous studies have shown that porcine circovirus 2 (PCV2) infection decreases the mitochondrial membrane potential and causes the elevation of reactive oxygen species (ROS), which may ultimately lead to mitochondrial apoptosis. However, whether PCV2 induce mitophagy remains unknown. Here we show that PCV2-induced mitophagy in PK-15 cells via Drp1 phosphorylation and PINK1/Parkin activation. PCV2 infection enhanced the phosphorylation of Drp1 and its subsequent translocation to mitochondria. PCV2-induced Drp1 phosphorylation could be suppressed by specific CDK1 inhibitor RO-3306, suggesting CDK1 as its possible upstream molecule. PCV2 infection increased the amount of ROS, up-regulated PINK1 expression, and stimulated recruitment of Parkin to mitochondria. N-acetyl-L-cysteine (NAC) markedly decreased PCV2-induced ROS, down-regulated Drp1 phosphorylation, and lessened PINK1 expression and mitochondrial accumulation of Parkin. Inhibition of Drp1 by mitochondrial division inhibitor-1 Mdivi-1 or RNA silencing not only resulted in the reduction of ROS and PINK1, improved mitochondrial mass and mitochondrial membrane potential, and decreased mitochondrial translocation of Parkin, but also led to reduced apoptotic responses. Together, our study shows that ROS induction due to PCV2 infection is responsible for the activation of Drp1 and the subsequent mitophagic and mitochondrial apoptotic responses.
Highlights
Porcine circovirus 2 (PCV2) is the major pathogen of several diseases, which are collectively referred to as Porcine-Circovirus-Related Diseases (PCVAD) [1]
Our study shows that reactive oxygen species (ROS) induction due to PCV2 infection is responsible for the activation of Drp1 and the subsequent mitophagic and mitochondrial apoptotic responses
To further address how ROS were involved in the Drp1 phosphorylation and PCV2‐induced mitophagy, we examined the changes of PINK1, Parkin, LC3II, Drp1, and p‐Drp1 in whole lysates of cells infected with PCV2 with or without NAC treatment
Summary
Porcine circovirus 2 (PCV2) is the major pathogen of several diseases, which are collectively referred to as Porcine-Circovirus-Related Diseases (PCVAD) [1]. As a single-stranded circular DNA virus of only approximately 1.7 kb, PCV2 contains three major open reading frames (ORFs): ORF1 coding for the replicase protein (Rep), ORF2 for the capsid protein (Cap), and ORF3 for a putative protein with pro-apoptotic activity [2,3]. We have found that PCV2 infection elicits autophagy via activation of CaMKKβ/AMPK/mTOR [5,6]. Autophagy is an intracellular event that degrades surplus cytoplasmic components [7,8]. Organelle-specific selective autophagy of the mitochondria (mitophagy) is a part of the macroautophagy that plays an important role in the quality control of mitochondria and the maintenance of cell homeostasis via selective engulfment of damaged mitochondria by autophagosomes and their subsequent degradation by lysosomes [12].
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