Reduced mitochondrial Rab32 impairs mitochondria-endoplasmic reticulum contacts and inhibits apoptosis in hepatocellular carcinoma cells.

Mitochondria-endoplasmic reticulum contacts (MERCs) play important roles in mitochondrial calcium homeostasis and apoptosis. Although MERC dysregulation has been implicated in the progression of various liver diseases, its role in hepatocellular carcinoma (HCC) remains poorly understood. Here, we report that mitochondria-localized Rab32 is required for maintaining MERC integrity in HCC cells. Mechanistically, Rab32 promotes the mitochondrial localization of protein kinase A (PKA), which facilitates protein tyrosine phosphatase-interacting protein 51 (PTPIP51) phosphorylation and maintains MERC integrity. Rab32 deficiency disrupts MERCs, reduces mitochondrial Ca²⁺ levels, and increases mitochondrial ROS accumulation. MERC restoration with a synthetic mitochondria-ER linker increased apoptosis and inhibited the proliferation of HCC cells. Together, these findings identify mitochondrial Rab32 as an important regulator of MERC integrity and apoptosis in HCC cells, suggesting that MERC stabilization may have potential for HCC treatment.