Chaperone-mediated autophagy sustains haematopoietic stem-cell function

Abstract

Activation of mostly quiescent hematopoietic stem cells (HSC) is a prerequisite for life-long blood production 1 , 2 . This process requires major molecular adaptations to meet the regulatory and metabolic requirements for cell division 3 – 8 . The mechanisms governing cellular reprograming upon stem cell activation and their subsequent return to quiescence are still not fully characterized. Here, we describe a role for chaperone-mediated autophagy (CMA) 9 , a selective form of lysosomal protein degradation, in sustaining adult HSC function. CMA is required for stem cell protein quality control and upregulation of fatty acid metabolism upon HSC activation. We identify that CMA activity decreases with age in HSC and show that genetic or pharmacological activation of CMA can restore functionality of old HSC. Together, our findings provide mechanistic insights into a new role for CMA in sustaining quality control, appropriate energetics and overall long-term hematopoietic stem cell function. Our work supports that CMA may be a promising therapeutic target to enhance hematopoietic stem cell function in conditions such as aging or stem cell transplantation.

Fatty acid desaturase activity in mature red blood cells and implications for blood storage quality

“…Historically, RBCs have been reported to take up fatty acids from circulation and, as such, the fatty acyl composition of RBC membrane lipids closely mirrors that of plasma and is significantly modulated by dietary intervention (e.g., supplementation of n‐3 fatty acids) 3,4 . Factors such as exercise, 5–7 aging, 8–10 nutrition, 11,12 and diseases—from neurological disease 13 to cancer 14,15 —have all been associated with alterations of RBC membrane fatty acyl composition. Because RBCs are incapable of de novo synthesis of long‐chain fatty acids such as palmitate, 16 they do rely on an acyl‐carnitine system in equilibrium with high‐energy acyl‐CoAs for the repairing of damaged fatty acyl groups, 17 a pathway that is referred to as the Lands cycle.…”

“…Evidence in cancer cells suggests a role of fatty acid desaturase (FADS) activity as a means to promote glycolysis by recycling NADH back to NAD+, as a compensatory mechanism to the Warburg phenotype—i.e., reliance on aerobic glycolysis—in highly proliferating cells 26 . Altered FADS activity is linked to impaired hematopoiesis in the context of aging; 10 however, it remains unclear if FADS could play a role in mature RBCs. Of note, RBC dependency on glycolysis as the sole source of energy production in the form of Adenosine Triphosphate (ATP) has helped to understand parallelisms between the Warburg phenotype of cancer cells and RBC metabolism 27 .…”

Cytoplasmic labile iron accumulates in aging stem cells perturbing a key rheostat for identity control

“…6,7 Various molecular mechanisms confer stem cell identity, ensure long-term maintenance and are known to be deregulated in aged stem cells. 8,9 How these programs are coordinated, particularly during cell division, and what triggers their ageing-associated dysfunction has been unknown.…”

A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress

“…Starvation induces non-selective autophagy which contributes to reclaiming molecular building blocks (Levine and Kroemer, 2019). In neurons and other long-lived cells, quality control of proteins and organelles is an additional critical function of autophagy (Dong et al, 2021;Evans and Holzbaur, 2020;Kroemer et al, 2010). The importance of the quality control function of starvation-independent basal autophagy was demonstrated by mutations in core autophagy components in mice and flies: cell-type specific loss of Atg5 or Atg7 triggers rapid neurodegeneration (Hara et al, 2006;Juhasz et al, 2007;Komatsu et al, 2006) or cardiac hypertrophy (Nakai et al, 2007).…”