Negative Selection of T-Lymphocytes Against Disease Causing Mitochondrial DNA Mutations

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Mitochondria are tiny membrane-bound cellular compartments with a vital role of saving our lives by providing energy. These small factories of ATP bear their own genetic material (mtDNA) which encodes 13 protein required by mitochondria themselves. Unlike nucleus, a single mitochondrion may contain many copies of mtDNA molecules with their nucleotide sequences different from each other. Such a co-existence of wild type and mutated mtDNA in cells or tissues is known as heteroplasmy. The level of heteroplasmy varies from person to person and has been shown to cause serious medical disorders with a wide range of clinical manifestations depending on the level of mutated mtDNA copies. One such disorder is mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) which results in a variety of symptoms including gastrointestinal dysmotility, maternally inherited deafness, diabetes and even multi-organ dysfunctions due to impaired mitochondrial translation and transcription.
Studies showed that almost 80% of the MELAS patients have a specific mutation in mtDNA referred to as A3243G. This mutation is linked with the abnormal activity of complex I of the electron transport chain in mitochondria.

Although heteroplasmy is significantly dependent on random drift and selection, there are tissue specific influences indicated by studies in human genetics. The degree of A3243G heteroplasmy varies significantly across all cell and tissue types, family members and time. This complicates the bulk analysis of heteroplasmy to separate the pathogenic mtDNA mutations in human tissues. Bulk heteroplasmy also does not explain the origin, variability, transmission and mechanisms of pathogenic mtDNA in different tissue types. Today, single cell heteroplasmy analysis is a promising technique to elucidate the underlying mechanisms, however, the studies involving patients have only been performed in a very limited number of non-somatic cells up till now.

In a recent study published in New England Journal of Medicine the researchers highlighted a reduced mitochondrial heteroplasmy in T cells as compared to all other blood cells of three unrelated patients of A3243G-associated MELAS. One of the patients had 39% A3243G heteroplasmy in whole blood and the second had 77% A3243G heteroplasmy in skeletal muscle, while the heteroplasmy in the third one was not quantified.

These researchers used advanced sequencing technologies to analyze the cell type and A3243G heteroplasmy in a variety of somatic cell lineages in the blood stream of unrelated patients.  By performing bulk heteroplasmy analysis they observed lower levels of heteroplasmy in T-cells as compared to other peripheral blood mononuclear cells (PBMCs). This observation reflects the purifying selection mechanism for A3243G mutations in the T-cell lineage.

The authors related that human T cells undergo purifying selection against A3243G mutations associated with pathogenic mtDNA in MELAS. This was also confirmed by bulk heteroplasmy analysis through FACS or bead-based negative selection in PBMCs from six other patients having A3243G heteroplasmy without stroke like episodes. However, whether the origin of this purifying selection is at cellular or organelle level is yet to be discovered.

T cells have a significant role in homeostasis and immunity which can be severely affected as a result of A3243G mutation-associated dysfunction of mitochondria. The negative selection of T cells against high heteroplasmy can be regarded as a compensatory mechanism against the inflammatory response of T cells to the presence of pathogenic mtDNA.

Understanding the dynamics of blood heteroplasmy is an intriguing challenge in science as it can be focused towards finding the impact of A3243G and other mtDNA mutations on the functions of immune cells. Also, due to the diversity of heteroplasmy across different cell types, investigating the specific cell lineages in blood has more prognostic and diagnostic value than blood heteroplasmy analysis. This research has also given a direction to future studies to explore the relationship of purifying selection to age-related decrease in A3243G and its effects on the overall immune system.  This study is also valuable in terms of inspiring new therapeutic approaches for identifying mechanisms involved in purifying selection against pathological mtDNA mutations.


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