Aberrant TRIM10β expression perturbs mitochondrial function and centrosome organization.

Abstract

Tripartite motif-containing protein 10β (TRIM10β) is a primate-specific isoform whose expression is restricted in most human tissues and regulated in a lineage- and stage-specific manner during erythropoiesis. However, the organelle-level mechanisms underlying the cytotoxic effects of dysregulated TRIM10β remain unclear. Here, we show that TRIM10β expression coincides with p38-p21 activation during late erythroid differentiation. Ectopic TRIM10β expression increased p38 phosphorylation and p21 expression in both erythroid and non-erythroid cells, whereas TRIM10β depletion attenuated late-stage p21 induction in differentiating erythroid cells. Proteomic analysis identified the mitochondrial carrier adenine nucleotide translocase 1 (ANT1) as a TRIM10β-interacting protein. Consistent with this interaction, TRIM10β localized to mitochondria, reduced ANT1-VDAC1 association and cellular ATP levels, and altered fission-associated signaling and mitochondrial membrane potential. In parallel, TRIM10β formed centrosome-proximal aggregates associated with defective centrosome organization, altered cell-cycle progression, γH2AX accumulation, and nuclear envelope deformation. These findings identify TRIM10β as a stage-restricted modulator of erythroid p38-p21 signaling and show that its dysregulated expression perturbs mitochondrial and centrosomal homeostasis, providing a mechanistic basis for its cytotoxicity.