Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
Authors
- Shuhei Koide (ORCID: https://orcid.org/0000-0001-8599-6115)
- Masayuki Yamashita (ORCID: https://orcid.org/0000-0001-9459-4329)
- Hiroyasu Nakano (ORCID: https://orcid.org/0000-0003-4843-1427)
- Yuriko Sorimachi
- Kenta Sumiyama (ORCID: https://orcid.org/0000-0001-8785-5439)
- Atsushi Iwama (ORCID: https://orcid.org/0000-0001-9410-8992)
- Keiyo Takubo (ORCID: https://orcid.org/0000-0002-1736-7592)
- Yu Fukuda (ORCID: https://orcid.org/0000-0001-6182-540X)
- Hiroshi Sagara (ORCID: https://orcid.org/0000-0003-3473-9850)
- Jinjing Yang
- Yuta Yamada
- Shin Murai
- Yuji Watanabe
- Akiho Saiki-Tsuchiya
Institutions
- Toho University (JP)
- St. Jude Children's Research Hospital (US)
- Tohoku University (JP)
- National Center for Global Health and Medicine (JP)
- Stem Cell Institute (PA)
- Nagoya University (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-06
- DOI
- https://doi.org/10.1038/s41467-026-71060-4
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- American Lebanese Syrian Associated Charities
- Kato Memorial Bioscience Foundation
- National Institutes of Health
- Japan Society for the Promotion of Science