1. Research background:
We are developing a novel dimension to the field of immunometabolism. We are studying how an infected cell actively rewires metabolic processes and organellar function to defend against‑and adapt to‑the challenge of microbial infection (rather than how immune cells adapt their metabolism to enable their effector functions). We then seek to understand whether the mechanisms we uncover also regulate cellular metabolic homeostasis independently of infection.
2. Research questions addresses by the group:
- How are organellar membranes remodeled during stress and ageing? In the course of our work on the metabolic competition between the human parasite Toxoplasma and mitochondria, we recently discovered large stuctures that we term SPOTs (structures positive for outer mitochondrial membrane proteins) that emerge from mitochondria during Toxoplasma infection. We seek to identify and structurally characterize the machinery required for SPOTs to emerge, and more broadly, understand their role in the remodeling of mitochondria during stress.
- Is the rewiring of mitochondrial metabolism an effector branch of innate immunity? We are combining genetic, metabolomic, and proteomic approaches in both host and parasite to determine how changes in cellular metabolism modulate microbial growth.
- How do mitochondria regulate cholesterol and steroid synthesis? The cell is an interconnected entity, yet the mechanisms that synchronize organellar function are little understood. We seek to define the crosstalk between mitochondria and the endoplasmic reticulum that regulates the synthesis of cholesterol and steroid hormones.
3. Possible projects:
- How are organellar membranes remodelled? Our preliminary work suggests that the shedding of outer mitochondrial membrane serves as a cellular response to safeguard mitochondrial function, and that a similar response may be observed in the endoplasmic reticulum. Using CRISPR/Cas9-enabled genetic screening and high throughput microscopy, we seek to identify the signals that induce and shape organellar remodeling during stress.
- How does the metabolic competition between mitochondria and microbes play out in vivo? We recently defined one example of metabolic competition between mitochondria and the human parasite Toxoplasma gondii. During infection, Toxoplasma exploits host lipophagy to gain access to cellular fatty acids essential for its growth. To counter this, host mitochondria fuse to enhance fatty acid uptake, limiting Toxoplasma access to a key host resource and thus restricting its growth. This work shows that mitochondria—essentially domesticated parasites—metabolically defend the cell during infection. Using cre-recombinase secreting parasites and various floxed genetic models, we will address whether mitochondrial fatty acid oxidation (and metabolism in general) is rewired to restrict microbial growth in vivo.
- How does diet affect microbial infection? It is well known that diet has profound affects on the microbiota, yet almost completely unknown how diet affects the progression of infection disease. We will address how diet affects parasitic infection.
4. Applied methods and model organisms:
- CRISPR screens
- High throughput microscopy
- Model organisms: Mus musculus, Toxoplasma gondii
5. Desirable skills and qualifications:
- Cell culture
- Willingness to work with mice
- Pernas, L., Bean, C., Boothroyd, J.C., and Scorrano, L. (2018) Mitochondria restrict Toxoplasma growth by limiting its fatty acids uptake. Cell Metabolism. 27(4):886-897. PMID: 29617646
- Pernas, L. (2021) Cellular metabolism in the defense against microbes. J Cell Science. 134(5):jcs252023. PMID: 33558420
- Li, X., Straub, J., Medeiros, T., Mehra, C., Stillger, K., Riemer, J., Burbridge, E., Adrain, C., and Pernas, L. Mitochondria shed large SPOTs during import stress to remodel their outer membrane. Under review at Science.