Mauro Corrado

Institute for Genetics (MNF), CMMC

Research Areas

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Mitochondrial Metabolism in Immunity, Inflammation, and Aging

The cellular metabolism, the energy substrates utilization preferences and tissue microenvironment composition are critical factors determining the efficiency of our immune cells to fight pathogens while controlling inflammation.

Research Focus

Cells constantly sense nutrient availability in their microenvironment, adapting function and survival to metabolic state. Driving this adaptation, mitochondria fine-tune their function in response to the dynamic metabolic requirements of the cell. Furthermore, mitochondria are central signaling hubs computing complex signaling networks. This extraordinary mitochondrial plasticity is critical to T cells, which constantly patrol tissues and traffick to and from lymphoid organs.

T cells coordinate multiple aspects of adaptive immunity throughout life including responses to pathogens, allergens and tumours. While doing so, T cells modulate metabolism depending on antigen-driven and microenvironmental signals. In recent years, the emerging field of immunometabolism started to unveil the role of metabolism in shaping immune function and how modulating cell or organismal metabolism affects immune cell differentiation and properties.

T cell cytotoxic and memory features are key for T cells to fight infections or cancer more efficiently and protecting us from their reoccurrence via long-lasting immune memory. Conversely, T cell function needs to be shut down in the context of autoimmune diseases to reduce disease severity. Research in the Corrado lab is focused on better understanding the metabolism of T cells during an immune response and how metabolism can be harnessed to modulate T cell function. To do so, we study the role of cardiolipin – the main phospholipid of the inner mitochondrial membrane – its synthesis and remodeling in immunity, inflammation and aging.

We study how T cell metabolism changes during an immune response with the aim to harness its modulation for therapeutic goals.

Our Goals

  • In our lab we aim at further investigating the molecular and environmental cues regulating metabolic programs in T cells during an immune response against pathogens and cancer and in autoimmune diseases. Our long-term goal is to establish a comprehensive understanding of the biology of mitochondrial plasticity in T cells in health and disease, opening up unique opportunities for therapeutic interventions. Understanding the regulatory circuit behind mitochondrial plasticity in T cells may reveal new strategies to counteract aging dependent decline in mitochondrial function and improve healthspan.
     
  • We have discovered that cardiolipin pool and profile are modulated by intrinsic and microenvironmental stimuli in CD8+ T cells and  that CD8-mediated adaptive immune responses are impaired when cardiolipin synthesis and remodeling are deficient. This work shows that the dynamic nature of cardiolipin drives T cell activation, differentiation, and adaptation to microenvironments. Indeed, cardiolipin synthesis allows T cell survival and adaptation in culture settings (like glucose restriction or specific cytokine and co-receptor stimulations) that invoke higher spare respiratory capacity (SRC), a measure of a cell’s ability to make extra ATP from OXPHOS upon increased energy demand. Moreover, T cells deficient in the cardiolipin-synthesizing enzyme PTPMT1 respond poorly to infections and fail to develop memory T cells. Conversely, increasing CL content in T cells improves their long-term survival and memory potential.

Key Publications

  1. Corrado M, Edwards-Hicks J, Villa M, Flachsmann LJ, Sanin DE, Jacobs M, Baixauli F, Stanczak M, Anderson E, Azuma M, Quintana A, Curtis JD, Clapes T, Grzes KM, Kabat AM, Kyle R, Patterson AE, Geltink RK, Amulic B, Steward CG, Strathdee D, Trompouki E, O'Sullivan D, Pearce EJ, Pearce EL (2020). Dynamic Cardiolipin Synthesis Is Required for CD8(+) T Cell Immunity. Cell Metab 32:981-995 e987. DOI: 10.1016/j.cmet.2020.11.003.
  2. Corrado M, Pearce EL (2022). Targeting memory T cell metabolism to improve immunity. J Clin Invest 132 DOI: 10.1172/JCI148546.
  3. Corrado M, Samardzic D, Giacomello M, Rana N, Pearce EL, Scorrano L (2021). Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism. Cell Death Differ 28:2194-2206. DOI: 10.1038/s41418-021-00747-6.
  4. Baixauli F, Piletic K, Puleston DJ, Villa M, Field CS, Flachsmann LJ, Quintana A, Rana N, Edwards-Hicks J, Matsushita M, Stanczak MA, Grzes KM, Kabat AM, Fabri M, Caputa G, Kelly B, Corrado M, Musa Y, Duda KJ, Mittler G, O'Sullivan D, Sesaki H, Jenuwein T, Buescher JM, Pearce EJ, Sanin DE, Pearce EL (2022). An LKB1-mitochondria axis controls T(H)17 effector function. Nature 610:555-561. DOI: 10.1038/s41586-022-05264-1.
  5. Humblin E, Korpas I, Lu J, Filipescu D, van der Heide V, Goldstein S, Vaidya A, Soares-Schanoski A, Casati B, Selvan ME, Gumus ZH, Wieland A, Corrado M, Cohen-Gould L, Bernstein E, Homann D, Chipuk J, Kamphorst AO (2023). Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1(+) PD-1(+) CD8 T cells. Sci Immunol 8:eadg0878. DOI: 10.1126/sciimmunol.adg0878.

Research Areas

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