Drp1-induced mitochondrial fission is a druggable vulnerability in multiple myeloma

Mitochondrial dynamics play a crucial role in essential cellular functions, including metabolism, which is vital for tumor cell growth and resistance to therapy. Our findings reveal that multiple myeloma (MM) cells exhibit a fragmented mitochondrial network, particularly in the more aggressive stages that are resistant to proteasome inhibitors (PIs). We observed that the DNM1L gene, which encodes the GTPase Drp1 - an important regulator of mitochondrial fission - was upregulated in MM plasma cells across multiple gene expression datasets, resulting in a hyperfragmented mitochondrial phenotype. DNM1L upregulation was associated with poor overall survival in patients included in the CoMMpass dataset.Targeting this excessive mitochondrial fragmentation, either through genetic knockdown of DNM1L or pharmacological inhibition using Drpitor1a, induced metabolic changes consistent with the suppression of oxidative phosphorylation. This, in turn, triggered anti-MM effects both in vitro and in vivo, and enhanced MM cell sensitivity to proteasome inhibitors. Mechanistically, Drp1 inhibition reprogrammed MM cell metabolism by blocking the lipogenesis pathway, leading to a form of cell death that exhibited features of both apoptosis and ferroptosis.