Abstract
Apoptosis is an important host defense mechanism against mycobacterial infection. However, the molecular mechanisms regulating apoptosis during mycobacterial infection are not well known. Recent reports suggest that bacterial infection regulates mitochondrial fusion and fission in various ways. Here, we investigated the role of mitochondria in Mycobacterium tuberculosis (Mtb)-infected macrophages. Mtb H37Rv (Rv) infection induced mitofusin 2 (MFN2) degradation, leading to mitochondrial fission. Interestingly, Mtb H37Ra (Ra) infection induced significantly greater mitochondrial fragmentation than Rv infection. Mtb-mediated Parkin, an E3 ubiquitin ligase, contributed to the degradation of MFN2. To evaluate the role of endoplasmic reticulum stress in the production of Parkin during Mtb infection, we analyzed Parkin production in 4-phenylbutyric acid (4-PBA)-pretreated macrophages. Pretreatment with 4-PBA reduced Parkin production in Mtb-infected macrophages. In contrast, the level of MFN2 production recovered to a level similar to that of the unstimulated control. In addition, Ra-infected macrophages had reduced mitochondrial membrane potential (MMP) compared to those infected with Rv. Interestingly, intracellular survival of mycobacteria was decreased in siMFN2-transfected macrophages; in contrast, overexpression of MFN2 in macrophages increased Mtb growth compared with the control.
Highlights
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), which can survive intracellularly [1]
We investigated whether Parkin is involved in mitofusin 2 (MFN2) production in Mtb-infected bone marrow-derived macrophages (BMDMs)
We showed that infection with attenuated Ra Mtb induced greater mitochondrial fragmentation than infection with Rv Mtb
Summary
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), which can survive intracellularly [1]. Mtb is inhaled in aerosol form and infects lung alveolar macrophages [2]. Many intracellular bacteria use host organelles such as the nucleus, mitochondria, Golgi, and endoplasmic reticulum (ER) [3]. Mtb changes the shape of mitochondria, leading to mitochondrial dysfunction [4]. Mitochondria are highly dynamic organelles that build the large interconnected intracellular networks responsible for cellular metabolism, differentiation, signaling, and death [5]. Mitochondrial dynamics are controlled by their fusion and fission [5]. Mitochondrial fusion involves the outer mitochondrial membrane GTPases mitofusin 1/2 (MFN1/2), and inner membrane GTPase optic atrophy 1 (OPA1) [5]. Mitochondrial fission requires mitochondrial fission 1 protein (FIS1) and GTPase dynamin-related protein 1 (DRP1), but the molecular details of fusion and fission are unknown [5].
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