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

Mitochondria are not only essential for cell metabolism and energy supply but they are also engaged in calcium homeostasis, reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondria disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very little data are available about 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, cristae thickness) in five leukemia cell lines (HEL, HL60, K562, KG1 and OCI-AML3) together with the functional assay of their respiratory profile. First of all, we show significant differences within basal respiration, maximal respiration, ATP production and spare respiratory capacity between our cell lines, confirming the various respiratory profiles between leukemia subtypes. Second, we highlight that these variations were obviously associated with significant inter-leukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1 characterized by the lowest number of mitochondria together with reduced cristae diameter displayed a very particularly deficient respiratory profile. In comparison, HEL and K562, both cell lines with high respiratory profiles, harbored the highest number of mitochondria/cells with high cristae diameters. We show the leukemia lines present ultrastructural alterations of their mitochondria likely to impact the regulatory pathways of cell mortality, such as the process of mitophagy or calcium homeostasis. Indeed, a significant disparity in the presence of Mitochondrial-derived vesicles (MDVs) precursors among AML cell lines, suggesting that leukemic cells displayed alteration of mitophagy, is also shown. For instance, few MDV precursors were observed in K562, carrying ASXL1mutation. Moreover, HL60 carried high levels of matrix granules and Mitochondria-associated Endoplasmic Reticulum membranes (MAMs) both implicated in calcium-dependent apoptosis. In conclusion, this study offers new and original data on mitochondria heterogeneity linked to the deregulation of respiration profiles in AMLs, suggesting that modifications of mitochondria shape and/or number in leukemic cells could be a targeted mechanism to regulate their proliferative potential.