S100A6 regulates intracellular and mitochondrial calcium buffering of hematopoietic stem cells fate options

Mitochondria are dynamic organelles involved in numerous physiological functions. Beyond their function in ATP production, mitochondria regulate cell death, reactive oxygen species generation and metabolism.

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Mitochondria also play a key role in the buffering of cytosolic calcium, and calcium transported into the matrix regulates mitochondrial metabolism. Indeed, our work has highlighted the importance of mitochondrial and cytosolic calcium homeostasis in regulating hematopoietic stem cells (HSCs) maintenance. We show that S100A6 govern the HSCs mitochondrial calcium levels through Akt phosphorylation regulation. Our work has established that cytoplasmic and mitochondrial calcium are key regulators of HSCs self-renewal and p-Akt is the prime target downstream of S100A6-calcium in activating HSCs regeneration. Akt is a known client protein of heat shock protein 90 (Hsp90). We also present that S100A6 integrates with Hsp90 in a p-Akt-dependent manner. We suggest that S100A6 might facilitate anchorage of mitochondria to F-actin and might act as an actin-mitochondrion crosslinker, as our data validate that S100A6 is not acting on the classical Golgi-ER pathway.

Our finding focuses on the S100A6 regulator in HSCs in normal hematopoiesis development. Our study has shed new light on the role of mitochondrial calcium dynamics in HSCs regulation through the modulation of p-Akt and Hsp90 production, as well as intracellular calcium signaling.

In general, the importance of good nutrition for a healthy blood system is well recognised and scientists have started to appreciate the complex metabolic interplay that regulates HSC activity and function. Until now, a number of exciting metabolic approaches have already been proposed to treat leukemia. Low levels of basal respiration also appear to have important roles in HSC quiescence and self-renewal activity, hence also suggesting critical functions for the TCA cycle and respiratory metabolic intermediates in HSC biology. Mitochondria are a powerhouse for all healthy cells and are needed in maintaining normal hematopoiesis.

Given the fast-pace of HSC metabolism research today, we are confident that new metabolic approaches to modulate healthy and malignant HSCs will soon be identified, and that in the long term these research efforts will improve the lives of patients with hematological diseases.

Better understanding the different metabolic requirements of HSCs and leukemic stem cells will help to identify new targetable metabolic vulnerabilities for the safe treatment and cure of leukemia.

Stefan Karlsson….Thank you for being my mentor. Tremendous of freedom and trust from you provide me a great foundation of confident and inner motivation to achieve this success. Simultaneously it is your 70 years old birthday, as one of your mentee, I am so proud and look up to you and a sincere salute to you, you are my scientific Godfather!



Tan Hooi Min Grahn

Assistant Researcher , Lund University