Mitochondria have recently been found to transcend their traditional role as ‘cellular powerhouses’ to emerge as central hubs for cellular metabolism and signaling. Indeed, mitochondria are involved in several cellular processes, including autophagy, apoptosis, cell proliferation and differentiation, and immune response regulation. Moreover, mitochondria are remarkably dynamic organelles as their morphology is constantly reshaped in perpetual cycles of fusion and fission, comprehensively referred to as ‘mitochondrial dynamics’. Mitochondrial fission is primarily enacted by dynamin-related protein 1 (Drp1), a cytosolic large GTPase that is actively recruited to the outer mitochondrial membrane (OMM) upon fission. In mammals, Drp1 recruitment relies on four binding partners located on the OMM: mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49 and MiD51), and mitochondrial fission 1 protein (Fis1). As opposed to Drp1, which has been extensively characterized as a master regulator of mitochondrial fission and implicated in several human pathologies, the role of Fis1 in mammalian mitochondrial fission and pathophysiology has remained controversial, with studies being limited to in vitro models and only recent evidence positioning Fis1 as a key factor in mitophagy, i.e. the process of selective degradation of mitochondria by autophagy. Recently, Fis1 has been implicated in acute myeloid leukemia (AML), a clonal malignancy of the myeloid lineage. Specifically, Fis1 appears to contribute to disease pathogenesis and progression by sustaining the function and the stem-like properties of leukemia stem cells (LSCs), a tumor cell subpopulation that drives the disease by replenishing the proliferating tumor cells (myeloblasts). Indeed, Fis1 is overexpressed in LSCs and seems to support their function through mitophagy. Therefore, we set out to investigate the physiological relevance of mitochondrial fission in the myeloid lineage by resorting to bone marrow-derived macrophages (BMDMs) from myeloid-specific Drp1 and Fis1 conditional knock-out mice, with the aim to unravel new molecular mechanisms that may potentially underlie AML development.

Mitochondria have recently been found to transcend their traditional role as ‘cellular powerhouses’ to emerge as central hubs for cellular metabolism and signaling. Indeed, mitochondria are involved in several cellular processes, including autophagy, apoptosis, cell proliferation and differentiation, and immune response regulation. Moreover, mitochondria are remarkably dynamic organelles as their morphology is constantly reshaped in perpetual cycles of fusion and fission, comprehensively referred to as ‘mitochondrial dynamics’. Mitochondrial fission is primarily enacted by dynamin-related protein 1 (Drp1), a cytosolic large GTPase that is actively recruited to the outer mitochondrial membrane (OMM) upon fission. In mammals, Drp1 recruitment relies on four binding partners located on the OMM: mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49 and MiD51), and mitochondrial fission 1 protein (Fis1). As opposed to Drp1, which has been extensively characterized as a master regulator of mitochondrial fission and implicated in several human pathologies, the role of Fis1 in mammalian mitochondrial fission and pathophysiology has remained controversial, with studies being limited to in vitro models and only recent evidence positioning Fis1 as a key factor in mitophagy, i.e. the process of selective degradation of mitochondria by autophagy. Recently, Fis1 has been implicated in acute myeloid leukemia (AML), a clonal malignancy of the myeloid lineage. Specifically, Fis1 appears to contribute to disease pathogenesis and progression by sustaining the function and the stem-like properties of leukemia stem cells (LSCs), a tumor cell subpopulation that drives the disease by replenishing the proliferating tumor cells (myeloblasts). Indeed, Fis1 is overexpressed in LSCs and seems to support their function through mitophagy. Therefore, we set out to investigate the physiological relevance of mitochondrial fission in the myeloid lineage by resorting to bone marrow-derived macrophages (BMDMs) from myeloid-specific Drp1 and Fis1 conditional knock-out mice, with the aim to unravel new molecular mechanisms that may potentially underlie AML development.

The role of the mitochondrial fission proteins Drp1 and Fis1 in the myeloid lineage

BARTOLAI, FRANCESCO
2022/2023

Abstract

Mitochondria have recently been found to transcend their traditional role as ‘cellular powerhouses’ to emerge as central hubs for cellular metabolism and signaling. Indeed, mitochondria are involved in several cellular processes, including autophagy, apoptosis, cell proliferation and differentiation, and immune response regulation. Moreover, mitochondria are remarkably dynamic organelles as their morphology is constantly reshaped in perpetual cycles of fusion and fission, comprehensively referred to as ‘mitochondrial dynamics’. Mitochondrial fission is primarily enacted by dynamin-related protein 1 (Drp1), a cytosolic large GTPase that is actively recruited to the outer mitochondrial membrane (OMM) upon fission. In mammals, Drp1 recruitment relies on four binding partners located on the OMM: mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49 and MiD51), and mitochondrial fission 1 protein (Fis1). As opposed to Drp1, which has been extensively characterized as a master regulator of mitochondrial fission and implicated in several human pathologies, the role of Fis1 in mammalian mitochondrial fission and pathophysiology has remained controversial, with studies being limited to in vitro models and only recent evidence positioning Fis1 as a key factor in mitophagy, i.e. the process of selective degradation of mitochondria by autophagy. Recently, Fis1 has been implicated in acute myeloid leukemia (AML), a clonal malignancy of the myeloid lineage. Specifically, Fis1 appears to contribute to disease pathogenesis and progression by sustaining the function and the stem-like properties of leukemia stem cells (LSCs), a tumor cell subpopulation that drives the disease by replenishing the proliferating tumor cells (myeloblasts). Indeed, Fis1 is overexpressed in LSCs and seems to support their function through mitophagy. Therefore, we set out to investigate the physiological relevance of mitochondrial fission in the myeloid lineage by resorting to bone marrow-derived macrophages (BMDMs) from myeloid-specific Drp1 and Fis1 conditional knock-out mice, with the aim to unravel new molecular mechanisms that may potentially underlie AML development.
2022
The role of the mitochondrial fission proteins Drp1 and Fis1 in the myeloid lineage
Mitochondria have recently been found to transcend their traditional role as ‘cellular powerhouses’ to emerge as central hubs for cellular metabolism and signaling. Indeed, mitochondria are involved in several cellular processes, including autophagy, apoptosis, cell proliferation and differentiation, and immune response regulation. Moreover, mitochondria are remarkably dynamic organelles as their morphology is constantly reshaped in perpetual cycles of fusion and fission, comprehensively referred to as ‘mitochondrial dynamics’. Mitochondrial fission is primarily enacted by dynamin-related protein 1 (Drp1), a cytosolic large GTPase that is actively recruited to the outer mitochondrial membrane (OMM) upon fission. In mammals, Drp1 recruitment relies on four binding partners located on the OMM: mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49 and MiD51), and mitochondrial fission 1 protein (Fis1). As opposed to Drp1, which has been extensively characterized as a master regulator of mitochondrial fission and implicated in several human pathologies, the role of Fis1 in mammalian mitochondrial fission and pathophysiology has remained controversial, with studies being limited to in vitro models and only recent evidence positioning Fis1 as a key factor in mitophagy, i.e. the process of selective degradation of mitochondria by autophagy. Recently, Fis1 has been implicated in acute myeloid leukemia (AML), a clonal malignancy of the myeloid lineage. Specifically, Fis1 appears to contribute to disease pathogenesis and progression by sustaining the function and the stem-like properties of leukemia stem cells (LSCs), a tumor cell subpopulation that drives the disease by replenishing the proliferating tumor cells (myeloblasts). Indeed, Fis1 is overexpressed in LSCs and seems to support their function through mitophagy. Therefore, we set out to investigate the physiological relevance of mitochondrial fission in the myeloid lineage by resorting to bone marrow-derived macrophages (BMDMs) from myeloid-specific Drp1 and Fis1 conditional knock-out mice, with the aim to unravel new molecular mechanisms that may potentially underlie AML development.
Mitochondria
Drp1
Fis1
File in questo prodotto:
File Dimensione Formato  
Bartolai_Francesco.pdf

accesso riservato

Dimensione 2.71 MB
Formato Adobe PDF
2.71 MB Adobe PDF

The text of this website © Università degli studi di Padova. Full Text are published under a non-exclusive license. Metadata are under a CC0 License

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/52141