MARCH5-Driven MFN2 Degradation Sustains Mitochondrial Fission and Drug Resistance in Multiple Myeloma

Mitochondrial dynamics, governed by the balance between fusion and fission, are critical for malignant plasma cell survival and therapeutic resistance in multiple myeloma (MM); however, the underlying molecular mechanisms remain poorly defined. Here, we investigated the role of the mitochondrial E3 ubiquitin ligase MARCH5 in MM proliferation, metabolic adaptation, and drug resistance, with a particular focus on its regulation of the mitochondrial fusion pathway. MARCH5 was significantly overexpressed in primary MM cells and established cell lines compared with healthy controls. Functional analyses revealed that MARCH5 interacts with the mitochondrial fusion protein mitofusin-2 (MFN2), promoting its ubiquitination and proteasomal degradation, thereby shifting mitochondrial dynamics toward fission. Silencing of MARCH5 stabilized MFN2, induced mitochondrial hyperfusion, impaired oxidative phosphorylation (OXPHOS), and triggered mitochondrial dysfunction and apoptosis. Similar phenotypic effects were observed following genetic overexpression or pharmacological activation of MFN2 using leflunomide, a repurposed FDA-approved drug, both in vitro and in MM xenograft models. Transcriptomic profiling of MARCH5-depleted cells revealed downregulation of OXPHOS-related pathways associated with venetoclax resistance. Consistently, MARCH5 knockdown or MFN2 induction enhanced venetoclax sensitivity and reduced mitochondrial respiration, whereas MARCH5 overexpression restored OXPHOS activity and attenuated drug responsiveness. Collectively, these findings identify the MARCH5–MFN2 axis as a key regulator of mitochondrial dynamics and metabolic fitness in MM and suggest that targeting this pathway may overcome venetoclax resistance and improve therapeutic outcomes in multiple myeloma.