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

Blood Advances - Tập 5 - Trang 4233-4255 - 2021
Kaori Saito1, Qi Zhang2, Haeun Yang1, Kotoko Yamatani1,3, Tomohiko Ai1, Vivian Ruvolo4, Natalia Baran2, Tianyu Cai2, Helen Ma2, Rodrigo Jacamo4, Vinitha Kuruvilla2, Junichi Imoto5, Sonoko Kinjo5, Kazuho Ikeo5, Kaori Moriya6, Koya Suzuki1,7, Takashi Miida1, Yong-Mi Kim8, Christopher P. Vellano9, Michael Andreeff4
1Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
2Section of Leukemia Biology Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan
4Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Center for Information Biology, National Institute of Genetics, Shizuoka, Japan
6Laboratory of Morphology and Image Analysis, Juntendo University Graduate School of Medicine, Tokyo, Japan
7Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan
8Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA
9TRACTION, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX

Tóm tắt

Abstract

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival, and they 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 expression of mitochondrial DNA and generation of mitochondrial reactive oxygen species indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, inhibition of OxPhos induced transfer of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via tunneling nanotubes under direct-contact coculture conditions. Inhibition of OxPhos also induced mitochondrial fission and increased functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, so we used electron microscopy to observe mitochondrial transport to the leading edge of protrusions of AML cells migrating toward MSCs. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased mitochondrial transfer of MSCs to AML cells triggered by OxPhos inhibition. 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.


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