Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival

Abstract

Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that Mycobacterium bovis ( M. bovis ) utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. M. bovis is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that M. bovis induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis . Moreover, the survival of M. bovis in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances M. bovis growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of M. bovis in the host. Abbreviations: BMDM: mouse bone marrow-derived macrophage; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; BCL2L13: BCL2-like 13 (apoptosis facilitator); CCCP: carbonyl cyanide m-cholorophenyl hydrazone; FUNDC1: FUN14 domain-containing 1; FKBP8: FKBP506 binding protein 8; HCV: hepatitis C virus; HBV: hepatitis B virus; IFN: interferon; L. monocytogenes: Listeria monocytogenes; M. bovis: Mycobacterium bovis ; Mtb: Mycobacterium tuberculosis ; Mdivi-1: mitochondrial division inhibitor 1; PINK1: PTEN-induced putative kinase 1; TBK1: TANK-binding kinase 1; TUFM: Tu translation elongation factor, mitochondrial; TEM: transmission electron microscopy

The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

“…It is well-established that Mdivi-1 is an inhibitor of mitophagy [ 40 , 41 ]. To further explore the role of mitophagy in mediating the alleviating effect of α-KG on the IL-1β-induced osteoarthritic phenotype of human chondrocytes, Mdivi-1 was used to treat IL-1β-induced chondrocytes combined with α-KG.…”

“…Faulkner et al further revealed that the beneficial effect of α-KG on ROS status was unlikely to be due to inducing antioxidant defense systems [ 63 ]. To further explore whether ROS changes are caused by mitophagy, IL-1β-induced osteoarthritic chondrocytes were co-treated with α-KG and Mdivi-1, a mitophagy inhibitor [ 40 , 41 ]. The results showed that Mdivi-1 eliminated the effects of α-KG on mitophagy and ROS production.…”

Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells

“…Pseudomonas aeruginosa can disrupt mitochondrial homeostasis in host cells, thus, activating mitophagy, which enhances the host defense against the toxic responses caused by its virulence factor Pyoverdin [36] . Mycobacterium bovis (M. bovis) infection induces mitophagy in murine macrophages, and induction of mitophagy improves M. bovis growth, whereas inhibition of mitophagy improves growth restriction [37] . We infected AGS and GES-1 cells with GZ7/CagA and GZ7/ΔCagA strains combined with mitophagy inducer (Olaparib), mitophagy inhibitor (BafA1), and NLRP3 in ammasome inhibitor (MCC950), respectively.…”

Antibodies Targeting the Cell Wall Induce Protection against Virulent Mycobacterium bovis Infection

“… M. bovis BCG strain Pasteur 1173P2 and M. bovis strain C68004 ( 21 ) were grown in Difco Middlebrook 7H9 broth (SKU 271310; Becton, Dickinson and Company) supplemented with 10% (vol/vol) oleic acid-albumin-dextrose-catalase (OADC) (SKU 212351; Becton, Dickinson and Company) and sodium pyruvate (DE-0342A; Biodee) at 4 mg/mL and with or without 0.05% (vol/vol) Tween 80 (P1754; Sigma) for 2 to 3 weeks at 37°C. In this study, the bacteria used to infect animals or cells were cultured with Tween 80 to make infection more accurate, and the bacteria used in other experiments were cultured without Tween 80 unless otherwise specified.…”