AI Article Synopsis
- Mitochondrial metabolite hexokinase 2 (HK2) is found in the nucleus of both leukaemic and normal haematopoietic stem cells, affecting their functions.
- Overexpressing HK2 in the nucleus enhances leukaemic stem cell traits and inhibits differentiation, while reducing HK2 promotes differentiation and reduces stem cell properties.
- HK2's nuclear presence relies on phosphorylation and specific transport mechanisms, impacting DNA repair and chemoresistance without its enzymatic function, highlighting a novel role for mitochondrial enzymes in regulating stem cells.
Article Abstract
Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203277 | PMC |
| http://dx.doi.org/10.1038/s41556-022-00925-9 | DOI Listing |
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