MFF marks a metabolic vulnerability of multiple myeloma

Increased mitochondrial fragmentation drives significant metabolic reprogramming that contributes to tumor progression. We explored the functional role of MFF (Mitochondrial Fission Factor), a key regulator of mitochondrial fragmentation, in the pathobiology of multiple myeloma (MM). MFF was found overexpressed in MM primary samples and cell lines, driving altered mitochondrial dynamics and metabolic reprogramming. MFF silencing inhibited MM cell proliferation, survival, and colony formation in vitro and in vivo. MFF overexpression promoted oxidative phosphorylation (OXPHOS) and a shift towards mitochondrial metabolism, while MFF knockdown favored glycolysis. These metabolic alterations were associated with alterations in lactate intracellular levels. Interestingly, lactate transporter inhibitors, in combination with MFF-targeting strategies, synergistically reduced MM cell viability and overcame proteasome inhibitor (PI) resistance. These findings highlight MFF as a key regulator of mitochondrial dynamics and metabolic adaptation in MM. Overall design: RNA samples extracted from H929 OE MFF and AMO-BZB shMFF myeloma cell lines were profiled for RNA seq analysis.