bims-mithem 2026-03-29 papers

on Mitochondria in Hematopoiesis

Issue of 2026–03–29
two papers selected by
Tim van Tienhoven, Erasmus Medical Center

Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.

Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]

Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.

Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.

Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

DOI: https://doi.org/10.1182/blood.2025031552
Cells. 2026 Mar 13. pii: 517. [Epub ahead of print]15(6):

Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.

Yusra Zarlashat, Anna Picca.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.

Keywords:  T-cell exhaustion; immune evasion; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15060517