bims-mithem 2025-12-14 papers

Issue of 2025–12–14
four papers selected by
Tim van Tienhoven, Erasmus Medical Center

Oncogenesis. 2025 Dec 08.

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Melina C Mancini, Cameron P McCall, Robert C Noland, Wagner S Dantas, Timothy D Heden.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.1038/s41389-025-00593-y

bioRxiv. 2025 Apr 26. pii: 2025.04.22.650071. [Epub ahead of print]

Influenza virus infection in the lungs leads to pancytopenia and defective immune cell differentiation program in the thymus and bone marrow.

Prajakta Shinde, Giovannino Silvestri, Panjamurthy Kuppusamy, Nicholas Stamatos, Chozha Vendan Rathinam.

Exaggerated inflammation and cytokine storm are hallmark features of influenza A virus (IAV)-induced respiratory diseases. While previous studies unequivocally demonstrated the pathophysiological consequences (multiorgan failure) of IAV-associated cytokine storm, it remains unknown if IAV-induced systemic inflammation impacts the fitness and differentiation of immune cells from hematopoietic stem cells (HSCs). Our data on lethal IAV-infected C57BL/6 wildtype mice after 10 days of infection indicated reduced monocyte- and lymphocyte- counts in the peripheral blood, and overall cellularity of spleen, thymus and lymph nodes. IAV- infection resulted in increased numbers of myeloid cells, CD8+ T cells, alveolar macrophages (AVMs), CD11b+ dendritic cells (DCs) & plasmacytoid DCs (pDCs), whereas decreased frequencies of CD103+ DCs, in the lungs of IAV-infected mice. Analysis of spleen and draining lymph nodes indicated reduced absolute numbers of B cells, T cells, monocytes and DCs after 10 days of lethal IAV infection. Thymic analysis indicated perturbed T cell differentiation and bone marrow (BM) data revealed impaired DC differentiation following IAV infection. Hematopoietic stem and progenitor cells (HSPCs) studies demonstrated an imbalanced distribution of HSCs, multipotent progenitors (MPPs), myeloid progenitors and DC progenitors within the BM niche. Mechanistic studies exhibited elevated levels of systemic inflammation and altered local pro-inflammatory milieu. Molecular analyses documented elevated levels of intracellular reactive oxygen species (ROS) at all stages of HSPC differentiation and increased mass of active mitochondria in HSPC subsets. In essence, our studies provide novel insights into mechanisms through which lethal IAV-infection induces deficiencies of the innate and adaptive immune system.

DOI: https://doi.org/10.1101/2025.04.22.650071

Exp Hematol. 2025 Dec 04. pii: S0301-472X(25)00621-6. [Epub ahead of print] 105332

Tumor necrosis factor from leukemic environment stimulates hematopoietic stem / progenitor cells toward megakaryocyte / myeloid lineage bias.

Hidekazu Nishikii, Riko Kikuchi, Takaharu Kimura, Mizuki Saito, Yusuke Kiyoki, Saki Tanaka, Yamato Sasaki, Takayasu Kato, Tatsuhiro Sakamoto, Mamiko Sakata-Yanagimoto, Naoshi Obara, Satoshi Yamazaki, Shigeru Chiba.

Acute myeloid leukemia (AML) is characterized by the proliferation of malignant myeloid progenitor cells and impairment of hematopoiesis. Although genetic abnormalities within leukemic cells have been investigated in detail, definitive explanations for the damage to the normal hematopoietic system are lacking. Here, we investigated the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow in AML. We evaluated the function of residual non-leukemic (nl)-hematopoietic stem / progenitor cell (HSPC) from the bone marrow of mice with MLL-AF9-induced AML. The nl-HSPC in the leukemic marrow showed a megakaryocyte (MgK) and myeloid-biased gene expression signature, with enrichment of TNF signaling and reduced repopulation ability. To investigate whether the upregulation of TNF signaling causes the MgK / myeloid lineage bias, we investigated the effects of TNF-α in normal hematopoietic stem cells (HSC) / HSPC under ex-vivo expansion condition. Single-cell transcriptome analysis of these cells revealed an increased frequency of cells expressing genes related to the MgK lineage and decreased repopulation capacity compared with those of ex vivo-expanded HSC / HSPC without TNF-α. Our data suggest that increased TNF-α in the leukemic bone marrow environment at least in part drives HSPC toward MgK / myeloid differentiation, resulting in the exhaustion of residual normal HSC / HSPC. These findings offer valuable insights into leukemic biology and normal hematopoiesis.

Keywords: Acute myeloid leukemia; bone marrow environment; hematopoietic stem progenitor cells; tumor necrosis factor

DOI: https://doi.org/10.1016/j.exphem.2025.105332

Nat Commun. 2025 Dec 12. 16(1): 11088

Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.

Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.

Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.

DOI: https://doi.org/10.1038/s41467-025-66042-x