Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition

Abstract

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia

“…Saito et al evaluated how the BM milieu modifies the response to OXPHOS reduction in AML by employing a complex I OXPHOS inhibitor, IACS-010759 [126]. Direct communications with BM stromal cells stimulated mitochondrial respiration and increased the transport of mitochondria that originated from MSCs to AML cells through TNTs.…”

Regulation of Malignant Myeloid Leukemia by Mesenchymal Stem Cells

“…In contrast to the classical Warburg effect, AML cells capture mitochondria from super-oxidized MSCs by leukemia-derived tunneling nanotubes to produce excess ATP, increase regrowing potential and get a better survival ( Moschoi et al, 2016 ; Marlein et al, 2017 ). This mitochondrial transfer function is important for AML cells to respond to killing resistance, oxidative stress restriction, cellular respiratory function, and healthy mitochondrial mass maintaining ( Burt et al, 2019 ; Saito et al, 2021 ) and can be terminated by CD38 antibody ( Mistry et al, 2021 ), but T-ALL cells reversely transfer its damaged mitochondria into MSCs for ROS elimination and chemoresistance ( Wang et al, 2018 ). Interestingly, the MSCs in leukemia are functionally distinct from normal MSCs, the confusion of leukemic MSCs could have cell-autonomous and non-cell-autonomous detrimental effects to adjacent healthy HSCs.…”

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

“…AML MSCs showed increased levels of ROS and oxidative stress, and the nuclear translocation of transcription factors associated with the expression of antioxidant enzymes [ 170 , 171 ]. These alterations induce modifications in MSC behaviour, allowing the transfer of mitochondria to the AML cells [ 170 , 172 , 173 , 174 ]. Interestingly, NADH-oxidase-2-dependent superoxide production in AML cells can drive the mitochondrial transfer [ 170 ] and induce a senescent phenotype in MSCs that is modulated by p16 and SASP [ 175 ].…”