Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells
Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoiesis-specific conditional-KO (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a led to HSC defects, including loss of HSC quiescence and self-renewal and increased differentiation. Mechanistically, we found that loss of Cpt1a resulted in elevated levels of mitochondrial respiratory chain complex components and their activity, as well as increased ATP production and accumulation of mitochondrial ROS in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate an essential role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.
Authors
- Chenhui He
- Hui Zeng (ORCID: https://orcid.org/0000-0001-8210-3465)
- Tian Li (ORCID: https://orcid.org/0000-0002-8281-4459)
- Paul R. Andreassen (ORCID: https://orcid.org/0000-0002-9760-1595)
- Mingzhe Pan
- Amy E. Armstrong (ORCID: https://orcid.org/0000-0002-7784-0476)
- Yu Luan (ORCID: https://orcid.org/0000-0003-1778-9071)
- Qili Shi
- Jie Bai (ORCID: https://orcid.org/0000-0002-7485-4450)
- Qianqian Jin (ORCID: https://orcid.org/0000-0001-5584-7581)
- Maiko Sezaki (ORCID: https://orcid.org/0000-0002-3286-2647)
- Victoria C. Pham (ORCID: https://orcid.org/0009-0009-9281-8806)
- Michihiro Hashimoto (ORCID: https://orcid.org/0000-0003-1673-3340)
- Shujun Liu (ORCID: https://orcid.org/0000-0002-2501-3946)
- Jue Li (ORCID: https://orcid.org/0000-0003-1602-8406)
- Gang Huang (ORCID: https://orcid.org/0000-0002-5457-5358)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Central South University (CN)
- The University of Texas at San Antonio Health Science Center (US)
- Urology San Antonio (US)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- MetroHealth Medical Center (US)
- Xiangya Hospital Central South University (CN)
- Southern Medical University (CN)
- Case Western Reserve University (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1172/jci184069
- Citations
- 5
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 8.85
Funders
- U.S. Department of Defense
- Cancer Prevention and Research Institute of Texas
- Cincinnati Children's Hospital Medical Center
- National Institutes of Health
- University of Texas Health Science Center at San Antonio