SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions
Creators: name: Kim, Tae Sung
name: Bae Jin, Yeung
name: Kim, Yi Sak
name: Kim, Sup
name: Kim, Jin Kyung
name: Lee, Hye-Mi
name: Suh, Hyun-Woo
name: Choe, Jin Ho
name: Jae Kim, Young
name: Koo, Bon-Sang
name: Kim, Han-Na
name: Jung, Mingyu
name: Lee, Sang-Hee
name: Kim, Don-Kyu
name: Chung, Chaeuk
name: Son, Ji-Woong
name: Min, Jung-Joon
name: Kim, Jin-Man
name: Deng, Chu-Xia
name: Kim, Hyun Seok
name: Lee, Sang-Rae
name: Jo, Eun-Kyeong
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Physiology
subject: Science Policy
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: SIRT3 (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 <i>sirt3<sup>−/-</sup></i> mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by <i>Mycobacterium tuberculosis</i> infection in <i>sirt3<sup>−/-</sup></i> 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 <i>sirt3<sup>−/-</sup></i> 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 <i>SIRT3</i> and <i>PPARA</i> were downregulated and inversely correlated with <i>TNF</i> (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. <b>Abbreviations:</b> Ab: antibody; BCG: <i>M. bovis</i> Bacillus Calmette–Guérin; Baf-A<sub>1</sub>: bafilomycin A<sub>1</sub>; 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&amp;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: <i>Mycobacterium tuberculosis</i>; 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