Kim, Tae Sung Bae Jin, Yeung Kim, Yi Sak Kim, Sup Kim, Jin Kyung Lee, Hye-Mi Suh, Hyun-Woo Choe, Jin Ho Jae Kim, Young 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 Kim, Hyun Seok Lee, Sang-Rae Jo, Eun-Kyeong SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions <p>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.</p> <p><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&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</p> SIRT3;autophagy;mitochondrial homeostasis;Mycobacterium tuberculosis;PPARA 2019-02-18
    https://tandf.figshare.com/articles/journal_contribution/SIRT3_promotes_antimycobacterial_defenses_by_coordinating_mitochondrial_and_autophagic_functions/7731197
10.6084/m9.figshare.7731197.v1