Metabolic determination of cell fate through selective inheritance of mitochondria

Döhla, Julia; Kuuluvainen, Emilia; Gebert, Nadja; Amaral, Ana Luísa; Englund, Johanna; Gopalakrishnan, Swetha; Konovalova, Svetlana; Nieminen, Anni I.; Salminen, Ella S; Muñumer, Rubén Torregrosa; Ahlqvist, Kati J.; Yang, Yang; Bui, Hien; Otonkoski, Timo; Käkelä, Reijo; Hietakangas, Ville; Tyynismaa, Henna; Ori, Alessandro; Katajisto, Pekka

doi:10.1038/s41556-021-00837-0

Cited by 51 publications

(38 citation statements)

References 59 publications

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“…Nonetheless, the increase in the mitochondrial density and changes in the quality suggests the presence of a compensatory mechanism, by which the mitochondrial number or the longevity of mitochondria and the quality of mitochondria compensate for the impaired mitochondrial activity as a consequence of the iron deficiency. This is in line with a recent observation indicating that the age of mitochondria determines their metabolic activity [ 35 ]. Moreover, in future studies, mitochondrial morphology could be investigated in PBMCs and the livers of the control and IDA rats to gain further knowledge about the underlying causes of the differences in the mitochondrial respiration observed in the present study.…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial Respiration in Response to Iron Deficiency Anemia: Comparison of Peripheral Blood Mononuclear Cells and Liver

et al. 2022

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Iron is an essential component for metabolic processes, including oxygen transport within hemoglobin, tricarboxylic acid (TCA) cycle activity, and mitochondrial energy transformation. Iron deficiency can thus lead to metabolic dysfunction and eventually result in iron deficiency anemia (IDA), which affects approximately 1.5 billion people worldwide. Using a rat model of IDA induced by phlebotomy, we studied the effects of IDA on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and the liver. Furthermore, we evaluated whether the mitochondrial function evaluated by high-resolution respirometry in PBMCs reflects corresponding alterations in the liver. Surprisingly, mitochondrial respiratory capacity was increased in PBMCs from rats with IDA compared to the controls. In contrast, mitochondrial respiration remained unaffected in livers from IDA rats. Of note, citrate synthase activity indicated an increased mitochondrial density in PBMCs, whereas it remained unchanged in the liver, partly explaining the different responses of mitochondrial respiration in PBMCs and the liver. Taken together, these results indicate that mitochondrial function determined in PBMCs cannot serve as a valid surrogate for respiration in the liver. Metabolic adaptions to iron deficiency resulted in different metabolic reprogramming in the blood cells and liver tissue.

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Section: Discussionsupporting

confidence: 93%

Mitochondrial Respiration in Response to Iron Deficiency Anemia: Comparison of Peripheral Blood Mononuclear Cells and Liver

et al. 2022

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“…Consequent heterogeneity in molecular content among cells can lead to different signaling responses, as measured by distinct IFN-γ and oncostatin M response in fibroblasts [47], and can lead to the presence of rare drug-resistant cells, such as those seen in melanoma [48]. Not only biomolecules (RNAs, proteins) but also entire organelles, such as mitochondria and membrane lipids can be asymmetrically partitioned, with implications in cell division rates and/or stemness traits [49,50]. In the EMT literature, to the best of our knowledge, the asymmetric partitioning of cell-fate determinant transcription factors (here, SNAIL)…”

Section: Discussionmentioning

confidence: 99%

Population Dynamics of Epithelial-Mesenchymal Heterogeneity in Cancer Cells

et al. 2022

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Phenotypic heterogeneity is a hallmark of aggressive cancer behaviour and a clinical challenge. Despite much characterisation of this heterogeneity at a multi-omics level in many cancers, we have a limited understanding of how this heterogeneity emerges spontaneously in an isogenic cell population. Some longitudinal observations of dynamics in epithelial-mesenchymal heterogeneity, a canonical example of phenotypic heterogeneity, have offered us opportunities to quantify the rates of phenotypic switching that may drive such heterogeneity. Here, we offer a mathematical modeling framework that explains the salient features of population dynamics noted in PMC42-LA cells: (a) predominance of EpCAMhigh subpopulation, (b) re-establishment of parental distributions from the EpCAMhigh and EpCAMlow subpopulations, and (c) enhanced heterogeneity in clonal populations established from individual cells. Our framework proposes that fluctuations or noise in content duplication and partitioning of SNAIL—an EMT-inducing transcription factor—during cell division can explain spontaneous phenotypic switching and consequent dynamic heterogeneity in PMC42-LA cells observed experimentally at both single-cell and bulk level analysis. Together, we propose that asymmetric cell division can be a potential mechanism for phenotypic heterogeneity.

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“…CCs and DSCs were seeded at a density of 1 × 10 5 cells/ml in total 30 ml of SILAC Advanced DMEM/F-12 Flex specially supplemented with 3 g/l stable isotopic labeled d -Glucose- 13 C 6 (in addition to the other media supplements described above) in Corning® Costar® TC-Treated T175 flasks for 2 h. Cells were subsequently treated with 0 or 3 μM AOAA for 24 h. Followingly, cells were washed twice in ice-cold 1X PBS formulated without Ca 2+ and Mg 2+ , detached by mechanical formulated without Ca 2+ and Mg 2+ , harvested by cell scraping, and pelleted by centrifugation at 4000 rpm for 5 min at 4 °C. Cell pellet was snap-frozen and stored at −80 °C till processed for analysis of 13 C-labeling of cellular metabolites as described [ [14] , [15] , [16] ]. Metabolites were extracted from cell using 400 μl of cold extraction solvent (acetonitrile:methanol:MQ, 40:40:20).…”

Section: Methodsmentioning

confidence: 99%

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Panagaki¹,

Pecze²,

Randi³

et al. 2022

Redox Biology

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Metabolic determination of cell fate through selective inheritance of mitochondria

Cited by 51 publications

References 59 publications

Mitochondrial Respiration in Response to Iron Deficiency Anemia: Comparison of Peripheral Blood Mononuclear Cells and Liver

Mitochondrial Respiration in Response to Iron Deficiency Anemia: Comparison of Peripheral Blood Mononuclear Cells and Liver

Population Dynamics of Epithelial-Mesenchymal Heterogeneity in Cancer Cells

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

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