Researchers from the MPI of Immunobiology and Epigenetics in Freiburg report that inter-organellar communication between phago-lysosomes and mitochondria has been shown to restrict the growth of bacteria such as Salmonella inside macrophages. Salmonella and other microorganisms have long developed ways to protect themselves from being digested by macrophages, causing severe typhoid and inflammation.

The new study, “TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages,” appears in Nature Metabolism.

“Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages,” the investigators wrote.

“By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB–Irg1–itaconate signaling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium.

“TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32–BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB’s role in autophagy-mediated pathogen degradation.

“Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella typhimurium burden in macrophages in vitro and in vivo.”

Macrophages have a prominent digestion organelle, the phago-lysosome, where engulfed microorganisms are commonly degraded into pieces and become inactivated. “The molecule TFEB is important for the regulation of the phago-lysosomal system. More recent evidence also suggested that TFEB supports the defense against bacteria,” said Max Planck group leader Angelika Rambold, PhD.

Rambold and her team wanted to understand how exactly TFEB mediates its antibacterial role in macrophages. They confirmed earlier findings showing that a broad range of microbes, bacterial, and inflammatory stimuli activate TFEB and thus the phago-lysosomal system.

“It made sense that pathogen signals trigger TFEB as macrophages need a more active digestion system quickly after they devour a meal of bacteria. But interestingly, the experiments also revealed an additional strong effect of TFEB activation on another intracellular organelle system—mitochondria. This was completely unexpected and novel to us,” explained Rambold.

Instructing mitochondria to increase antimicrobial activity

By using a range of research tools, including metabolomics, molecular biology, and imaging techniques, the Max Planck group identified the pathway controlling an unexpected crosstalk between lysosomes and mitochondria.

“Macrophages make use of extensive inter-organellar communication: the lysosome activates TFEB, which shuttles into the nucleus where it controls the transcription of a protein called IRG1,” continued Rambold. “This protein is imported into mitochondria, where it acts as a major enzyme to produce the antimicrobial metabolite itaconate. We speculated that activating this pathway could be used to target certain bacterial species, such as Salmonella.”

Salmonella can escape the degradation by the phago-lysosomal system. They manage to grow inside macrophages, which can lead to the spreading of these bacteria to several organs in an infected body,” added Alexander Westermann, PhD, collaborating scientist from the University of Würzburg.

When the researchers activated TFEB in infected macrophages in mice, the TFEB-Irg1-itaconate pathway inhibited the growth of Salmonella inside the cells. These data show that the lysosome-to-mitochondria interplay represents an antibacterial defense mechanism to protect the macrophage from being exploited as a bacterial growth niche.

In light of the increasing emergence of multi-drug resistant bacteria, with more than 10 million expected deaths per year by 2050 according to the various expert groups, it becomes important to identify new strategies to control bacterial infections that escape immune mechanisms.

Utilizing the TFEB-Irg1-itaconate pathway or itaconate itself to treat infections caused by itaconate-sensitive bacteria might be a promising path. According to the scientists from Freiburg and Würzburg, more work, however, is needed to assess whether these new intervention points can be successfully applied to humans.

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