Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency

TL;DR

This study shows that changes in mitochondrial DNA and energy production are key during cell reprogramming into stem cells.

Contribution

The study identifies thymidine kinase 2 (TK2) as a key player in mitochondrial DNA changes during cell reprogramming.

Findings

TK2 levels decrease during reprogramming, leading to reduced mitochondrial DNA copy number.

Lower TK2 expression shifts energy production from oxidative phosphorylation to glycolysis in pluripotent stem cells.

Reduced TK2 and mitochondrial DNA are linked to the metabolic changes needed for pluripotency.

Abstract

Somatic cell reprogramming into human induced pluripotent stem cells entails significant intracellular changes, including modifications in mitochondrial metabolism and a decrease in mitochondrial DNA copy number. However, the mechanisms underlying this decrease in mitochondrial DNA copy number during reprogramming remain unclear. Here we aimed to elucidate these underlying mechanisms. Through a meta-analysis of several RNA sequencing datasets, we identified genes responsible for the decrease in mitochondrial DNA. We investigated the functions of these identified genes and assessed their regulatory mechanisms. In particular, the expression of the thymidine kinase 2 gene (TK2), located in the mitochondria and required for mitochondrial DNA synthesis, is decreased in human pluripotent stem cells as compared with its expression in somatic cells. TK2 was significantly downregulated during reprogramming and markedly upregulated during differentiation. Collectively, this decrease in TK2 levels induces a decrease in mitochondrial DNA copy number and contributes to shaping the metabolic characteristics of human pluripotent stem cells. However, contrary to our expectations, treatment with a TK2 inhibitor impaired somatic cell reprogramming. These results suggest that decreased TK2 expression may result from metabolic conversion during somatic cell reprogramming.

Induced pluripotent stem (iPS) cells are special cells created by reprogramming regular body cells. Researchers explored how these cells change their energy production methods during reprogramming. The study focused on a protein called thymidine kinase 2 (TK2), which is important for maintaining mitochondrial DNA (mtDNA). Mitochondria are the cell’s powerhouses, and their DNA is crucial for energy production. Researchers used human cell lines to study how TK2 affects mtDNA during reprogramming. They found that, as cells become iPS cells, TK2 levels drop, leading to reduced mtDNA and a shift in energy production from oxidative phosphorylation to glycolysis. Results suggest that reducing TK2 and mtDNA is key for cells to gain pluripotency. This shift helps support the rapid growth and development of iPS cells. Understanding this process could improve stem cell therapies and regenerative medicine in the future.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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