Mitochondrial E3-ubiquitin ligase March5 regulates mitochondrial fusion and venetoclax sensitivity in MM

Emerging evidence indicates that mitochondrial fission and fusion processes are imbalanced in multiple myeloma (MM), likely due to defective post-translational regulation of key mediators. In this study, we explored the functional role of the mitochondrial E3 ubiquitin ligase Membrane Associated Ring-CH-Type Finger 5 (March5), a novel regulator of mitochondrial dynamics, in MM cell proliferation, metabolic reprogramming, and drug resistance.March5 silencing led to elongated mitochondria, as observed via transmission electron microscopy (TEM), suggesting a shift toward mitochondrial fusion. This was further supported by increased expression of the fusion protein MFN2 following March5 knockdown, while March5 overexpression (OE) reduced MFN2 protein stability. Transcriptomic profiling of March5-depleted cells revealed downregulation of pathways related to the mitochondrial electron transport chain (ETC) and ATP production -- processes previously linked to resistance to the BCL-2 inhibitor venetoclax.Functionally, both March5 silencing and MFN2 overexpression enhanced sensitivity to venetoclax, whereas March5 overexpression diminished its anti-myeloma activity. At the metabolic level, March5 knockdown or venetoclax treatment reduced oxidative phosphorylation (OXPHOS), while March5 overexpression increased OXPHOS, counteracting venetoclax-induced metabolic stress.