Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network of continuously changing shape, size, and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin Histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme which is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondrias. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number, and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation and mitochondrial complex I assembly, and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement, and function. Finally, we discovered that SETD3 levels are regulated by ECM stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.

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