Mitochondrial dynamics in the multiple myeloma niche
2Research Institute, Meir Medical Center, Israel
3Hematology Unit, Meir Medical Center, Israel
4Autoimmunity Laboratory, Meir Medical Center, Israel
5Orthopedics Department, Meir Medical Center, Israel
6Bioinformatics Unit, G.S.W. Faculty of Life Sciences, Tel Aviv University, Israel
7Sackler faculty of Medicine, Tel Aviv University, Israel
Background: Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where they interact with mesenchymal stem cells (MSCs). This crosstalk depends on MSCs` source (normal donors or MM patients). MM-MSCs proteomics displayed enriched metabolic processes, particularly mitochondrial, compared to ND-MSCs. Recent reports described mitochondrial trafficking from BM-MSCs to adjacent MM cells, yet its significance remains obscure. Mitochondria (mt) are critical to cellular design and regulated by fission, fusion and degradation (mitochondrial dynamics). We focused on the role of BM-MSCs mitochondrial dynamics in the MM niche.
Methods: ND and MM-MSCs were analyzed for proteomics (mass spectrometry, bioinformatics), ATP production rate (Seahorse XF Analyzer), mitochondrial dynamics, mass and trafficking (immunoblotting, mitotrackers, flow cytometry, confocal microscopy). We determined phenotype of mt recipient MM cells (MM1S/U266) co-cultured with BM-MSCs or artificially inserted with mt isolated from BM-MSCs, termed BM-MSCs(mtiso) (trypan blue, immunoblotting).
Results: Isolated mt proteome of MM-MSCs and ND-MSCs varied significantly. MM-MSCs showed increased OXPHOS-ATP production compared to ND-MSCs, yet mitochondrial mass and self-mediated trafficking (24h,co-culture) into MM1S/U266 were similar. Preliminary results show ↓fission/fusion ratio in MM-MSCs versus ND-MSCs (fission factors:↓55% Mff, ↓37% phospho-DRP1(Ser616), fusion factor: ↑68% Opa1; p<0.05). Artificial transfer of MM-MSCs(mtiso) caused excessive MM1S death compared to ND-MSCs(mtiso) (24-48h,↑>150%; p<0.0005) with elevated autophagy factor LC3II (↑68%) and DRP1 (↑80%)(p<0.05).
Conclusions: These data portray a central role for mt in MM-MSCs dialogue with dynamics critically involved and contingent on ND or MM-MSCs origin. In ongoing studies, we aim to determine the significance of mt dynamics to MM design, monitoring and treatment.