SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host <i>Salmonella</i> pH Balance during Infection

Mitochondria are important organelles that regulate energy homeostasis. Mitochondrial health and dynamics are crucial determinants of the outcome of several bacterial infections. SIRT3, a major mitochondrial sirtuin, along with SIRT1 regulates key mitochondrial functions. This led to considerable interest in understanding the role of SIRT1 and SIRT3 in governing mitochondrial functions during <i>Salmonella</i> infection. Here, we show that loss of SIRT1 and SIRT3 function either by shRNA-mediated knockdown or by inhibitor treatment led to increased mitochondrial dysfunction with alteration in mitochondrial bioenergetics alongside increased mitochondrial superoxide generation in <i>Salmonella-</i>infected macrophages. Consistent with dysfunctional mitochondria, mitophagy was induced along with altered mitochondrial fusion-fission dynamics in <i>S. typhimurium</i><i>-</i>infected macrophages. Additionally, the mitochondrial bioenergetic alteration promotes acidification of the infected macrophage cytosolic pH. This host cytosolic pH imbalance skewed the intraphagosomal and intrabacterial pH in the absence of SIRT1 and SIRT3, resulting in decreased SPI-2 gene expression. Our results suggest a novel role for SIRT1 and SIRT3 in maintaining the intracellular <i>Salmonella</i> niche by modulating the mitochondrial bioenergetics and dynamics in the infected macrophages.