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SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions
Kim,Tae Sung1,2,3; Jin,Yeung Bae4; Kim,Yi Sak1,2,3; Kim,Sup1,2,3; Kim,Jin Kyung1,2,3; Lee,Hye Mi1; Suh,Hyun Woo1,3; Choe,Jin Ho1,2,3; Kim,Young Jae1,2,3; Koo,Bon Sang4; Kim,Han Na4; Jung,Mingyu5; Lee,Sang Hee6; Kim,Don Kyu7; Chung,Chaeuk3,8; Son,Ji Woong9; Min,Jung Joon10; Kim,Jin Man3,5; Deng,Chu Xia11; Kim,Hyun Seok12; Lee,Sang Rae4; Jo,Eun Kyeong1,2,3
Source PublicationAutophagy
AbstractSIRT3 (sirtuin 3), a mitochondrial protein deacetylase, maintains respiratory function, but its role in the regulation of innate immune defense is largely unknown. Herein, we show that SIRT3 coordinates mitochondrial function and macroautophagy/autophagy activation to promote anti-mycobacterial responses through PPARA (peroxisome proliferator activated receptor alpha). SIRT3 deficiency enhanced inflammatory responses and mitochondrial dysfunction, leading to defective host defense and pathological inflammation during mycobacterial infection. Antibody-mediated depletion of polymorphonuclear neutrophils significantly increased protection against mycobacterial infection in sirt3 mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by Mycobacterium tuberculosis infection in sirt3 macrophages. Notably, SIRT3 was essential for the enhancement of PPARA, a key regulator of mitochondrial homeostasis and autophagy activation in the context of infection. Importantly, overexpression of either PPARA or TFEB (transcription factor EB) in sirt3 macrophages recovered antimicrobial activity through autophagy activation. Furthermore, pharmacological activation of SIRT3 enhanced antibacterial autophagy and functional mitochondrial pools during mycobacterial infection. Finally, the levels of SIRT3 and PPARA were downregulated and inversely correlated with TNF (tumor necrosis factor) levels in peripheral blood mononuclear cells from tuberculosis patients. Collectively, these data demonstrate a previously unappreciated function of SIRT3 in orchestrating mitochondrial and autophagic functions to promote antimycobacterial responses. Abbreviations: Ab: antibody; BCG: M. bovis Bacillus Calmette–Guérin; Baf-A: bafilomycin A; BMDMs: bone marrow-derived macrophages; CFU: colony forming unit; CXCL5: C-X-C motif chemokine ligand 5; EGFP: enhanced green fluorescent protein; ERFP: enhanced red fluorescent protein; FOXO3: forkhead box O3; HC: healthy controls; H&E: haematoxylin and eosin; HKL: honokiol; IHC: immunohistochemistry; IL1B: interleukin 1 beta; IL6: interleukin 6; IL12B: interleukin 12B; MDMs: monocyte-derived macrophages; MMP: mitochondrial membrane potential; Mtb: Mycobacterium tuberculosis; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffered saline; PMN: polymorphonuclear neutrophil; PPARA: peroxisome proliferator activated receptor alpha; ROS: reactive oxygen species; SIRT3: sirtuin 3; TB: tuberculosis; TEM: transmission electron microscopy; TFEB: transcription factor EB; TNF: tumor necrosis factor.
Keywordautophagy mitochondrial homeostasis Mycobacterium tuberculosis PPARA SIRT3
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Cited Times [WOS]:48   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Department of Microbiology,Chungnam National University School of Medicine,Daejeon,South Korea
2.Department of Medical Science,Chungnam National University School of Medicine,Daejeon,South Korea
3.Infection Control Convergence Research Center,Chungnam National University School of Medicine,Daejeon,South Korea
4.National Primate Research Center,Korea Research Institute of Bioscience and Biotechnology,Cheongju,South Korea
5.Department of Pathology,Chungnam National University School of Medicine,Daejeon,South Korea
6.Institute of Molecular Biology & Genetics,Seoul National University,Seoul,South Korea
7.Department of Molecular Biotechnology,Chonnam National University,Gwangju,South Korea
8.Division of Pulmonary and Critical Care,Department of Internal Medicine,Chungnam National University School of Medicine,Daejeon,South Korea
9.Department of Internal Medicine,Konyang University,Daejeon,South Korea
10.Department of Nuclear Medicine,Chonnam National University Medical School,Gwangju,South Korea
11.Faculty of Health Sciences,University of Macau,Macao
12.Department of Bioinspired Science,Ewha Womans University,Seoul,South Korea
Recommended Citation
GB/T 7714
Kim,Tae Sung,Jin,Yeung Bae,Kim,Yi Sak,et al. SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions[J]. Autophagy,2019,15(8):1356-1375.
APA Kim,Tae Sung.,Jin,Yeung Bae.,Kim,Yi Sak.,Kim,Sup.,Kim,Jin Kyung.,Lee,Hye Mi.,Suh,Hyun Woo.,Choe,Jin Ho.,Kim,Young Jae.,Koo,Bon Sang.,Kim,Han Na.,Jung,Mingyu.,Lee,Sang Hee.,Kim,Don Kyu.,Chung,Chaeuk.,Son,Ji Woong.,Min,Jung Joon.,Kim,Jin Man.,Deng,Chu Xia.,...&Jo,Eun Kyeong.(2019).SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions.Autophagy,15(8),1356-1375.
MLA Kim,Tae Sung,et al."SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions".Autophagy 15.8(2019):1356-1375.
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