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Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles

2021; Elsevier BV; Volume: 98; Linguagem: Inglês

10.1016/j.exphem.2021.03.001

1873-2399

Julie Mondet, Caroline Lo Presti, Simon Chevalier, Anne Bertrand, Sylvie Tondeur, Sandrine Blanchet, Anne Mc Leer, Karin Pernet‐Gallay, Pascal Mossuz,

Cancer, Hypoxia, and Metabolism

•The presence of MAMs and matrix granules in AML cell lines is evidence that there are active communication processes between endoplasmic reticulum and mitochondria in AML. •HL60 carrying high levels of matrix granules and MAMs in favor of conserved mitochondria endoplasmic reticulum communication has a higher sensitivity to drugs targeting mitochondria (rotenone/antimycin). •Conversely, K562, carrying the ASXL1 mutation, exhibits a decrease in the numbers of matrix granules, MAM, and MDV precursors associated with chemoresistance to drugs targeting mitochondria. •Through transcriptomic analysis, we confirm the implication of ASXL1 mutation in mitochondria–ER contact deficiency, thereby providing a potential explanation of the worse prognostic value of ASXL1 mutation. Mitochondria not only are essential for cell metabolism and energy supply but are also engaged in calcium homeostasis and reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondrial disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very few data are available on the deregulation of their number and/or shape in leukemic cells, despite the evident link between ultrastructure and function. In this context, we analyzed the ultrastructural mitochondrial parameters (number per cell, mitochondria area, number of cristae/mitochondria, cristal thickness) in five leukemia cell lines (HEL, HL60, K562, KG1, and OCI-AML3) together with the functional assay of their respiratory profile. First, we describe significant differences in basal respiration, maximal respiration, ATP production, and spare respiratory capacity between our cell lines, confirming the various respiratory profiles among leukemia subtypes. Second, we highlight that these variations are obviously associated with significant interleukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1, characterized by the smallest number of mitochondria together with reduced cristal diameter, had a particularly deficient respiratory profile. In comparison, the HEL and K562 cell lines, both with high respiratory profiles, harbored the largest number of mitochondria/cells with high cristal diameters. Moreover, we report that K562, carrying the ASXL1 mutation, presents significant mitochondria–endoplasmic reticulum deficiency reflected by decreases in the numbers of matrix granules and mitochondria-associated endoplasmic reticulum membrane (MAM) and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulatory pathways of cell mortality via the processes of mitophagy and calcium homeostasis. Contrarily, HL60 carried high levels of matrix granules and MAMs and had a higher sensitivity to drugs targeting mitochondria (rotenone/antimycin). We confirm the implication of ASXL1 mutation in this mitochondria dysregulation through the study of transcript expression (from 415 patients with public data) involved in three mitochondrial pathways: (1) endoplasmic reticulum–mitochondria contacts (MAMs), (2) matrix granule homeostasis, and (3) MDV precursor production. Our study offers new and original data on mitochondria structural alterations linked to deregulation of respiration profiles in AMLs and some genetic characteristics, suggesting that modifications of mitochondrial shape and/or number in leukemic cells participate in chemoresistance and could be a targeted mechanism to regulate their proliferative potential. Mitochondria not only are essential for cell metabolism and energy supply but are also engaged in calcium homeostasis and reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondrial disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very few data are available on the deregulation of their number and/or shape in leukemic cells, despite the evident link between ultrastructure and function. In this context, we analyzed the ultrastructural mitochondrial parameters (number per cell, mitochondria area, number of cristae/mitochondria, cristal thickness) in five leukemia cell lines (HEL, HL60, K562, KG1, and OCI-AML3) together with the functional assay of their respiratory profile. First, we describe significant differences in basal respiration, maximal respiration, ATP production, and spare respiratory capacity between our cell lines, confirming the various respiratory profiles among leukemia subtypes. Second, we highlight that these variations are obviously associated with significant interleukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1, characterized by the smallest number of mitochondria together with reduced cristal diameter, had a particularly deficient respiratory profile. In comparison, the HEL and K562 cell lines, both with high respiratory profiles, harbored the largest number of mitochondria/cells with high cristal diameters. Moreover, we report that K562, carrying the ASXL1 mutation, presents significant mitochondria–endoplasmic reticulum deficiency reflected by decreases in the numbers of matrix granules and mitochondria-associated endoplasmic reticulum membrane (MAM) and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulatory pathways of cell mortality via the processes of mitophagy and calcium homeostasis. Contrarily, HL60 carried high levels of matrix granules and MAMs and had a higher sensitivity to drugs targeting mitochondria (rotenone/antimycin). We confirm the implication of ASXL1 mutation in this mitochondria dysregulation through the study of transcript expression (from 415 patients with public data) involved in three mitochondrial pathways: (1) endoplasmic reticulum–mitochondria contacts (MAMs), (2) matrix granule homeostasis, and (3) MDV precursor production. Our study offers new and original data on mitochondria structural alterations linked to deregulation of respiration profiles in AMLs and some genetic characteristics, suggesting that modifications of mitochondrial shape and/or number in leukemic cells participate in chemoresistance and could be a targeted mechanism to regulate their proliferative potential.