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  • Creating the Future

    The Hector Fellow Academy initiates innovative research projects on latest scientific problems.

Mitochondrial DNA mutational landscape in human T cells

Yu-Hsin Hsieh – Hector RCD Awardee Leif Ludwig

T cell differentiation and function are tightly regulated by numerous cellular processes, including cellular metabolism, which can be significantly affected by mitochondrial DNA (mtDNA) mutations. However, the impact of mtDNA mutational burden on T cell differentiation and functional heterogeneity remains poorly understood. Thus, this project aims to characterize the mtDNA mutational landscape and its functional consequences in human T cells using single-cell multi-omics approaches.

Naïve T cells undergo clonal expansion after encountering antigens and further differentiate into effector cells. After the clearance of infected cells, a small proportion of T cells further differentiate into long-lived memory populations. Recent advances in single-cell genomics have unraveled plasticity and functional heterogeneity as well as novel subsets of human T cells. Moreover, studies have revealed the important role of mitochondrial function on T cell differentiation and function.

Mitochondria are known as the cell's powerhouse, carrying their own genomic DNA (mitochondrial DNA, mtDNA), which encodes 13 for proteins of the respiratory chain and their translational machinery. Thus, mtDNA mutations can compromise cellular metabolism and function. Nevertheless, how mtDNA mutational burden and heteroplasmy affect T cell differentiation and function remains unclear. Here, I hypothesize that T cells will manifest cell fate and functional biases in response to the overall mutational burden of mtDNA mutations.

Recently, Dr. Leif Ludwig, the Hector Research Career Development Awardee 2020, developed a novel multi-omics technique, known as DOGMA-seq, enabling the sequencing of the mitochondrial genome, the assessment of chromatin accessibility, gene expression, and protein profiling simultaneously in single cells. In this doctoral project, we will leverage this technique to decipher the impact of the mitochondrial genome mutational landscape on T cell differentiation and function.

 

Description: Mapping and characterizing the mitochondrial mutational landscape and functional consequences in human T cells using single-cell multi-omics