| Title: |
Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia |
| Authors: |
Gianni’, Maurizio; Goracci, Laura; Schlaefli, Anna; Di Veroli, Alessandra; Kurosaki, Mami; Guarrera, Luca; Bolis, Marco; Foglia, Marika; Lupi, Monica; Tschan, Mario; Cruciani, Gabriele; Terao, Mineko; Garattini, Enrico |
| Source: |
Gianni’, Maurizio; Goracci, Laura; Schlaefli, Anna; Di Veroli, Alessandra; Kurosaki, Mami; Guarrera, Luca; Bolis, Marco; Foglia, Marika; Lupi, Monica; Tschan, Mario; Cruciani, Gabriele; Terao, Mineko; Garattini, Enrico (2022). Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia. Cell death & disease, 13(1), p. 30. Nature Publishing Group 10.1038/s41419-021-04476-z |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2022 |
| Collection: |
BORIS (Bern Open Repository and Information System, University of Bern) |
| Subject Terms: |
570 Life sciences; biology; 610 Medicine & health |
| Description: |
The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://boris.unibe.ch/164390/ |
| Availability: |
https://boris.unibe.ch/164390/1/Gianni-_et_al-2022-Cell_Death___Disease.pdf; https://boris.unibe.ch/164390/ |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.3E70F55B |
| Database: |
BASE |