Mitochondrial Translocation of TFEB Regulates Complex I and Inflammation

TFEB is an important transcriptional regulator of autophagy, lysosome biogenesis, and immunity, whose activity is regulated by cytosol-to-nuclear translocation through downregulation of the nutrient sensor mTOR. Here we show that TFEB has a non-transcriptional role in mitochondria essential for the regulation of mitochondrial complex I and inflammation. Proteomic analysis revealed that TFEB co-precipitates with several mitochondrial proteins, whose interactions are perturbed in S. Typhimurium infected cells. High resolution microscopy and biochemical experiments further confirmed that TFEB localizes in the mitochondrial matrix. TFEB mitochondrial translocation depends on a conserved TOMM20 binding motif within the protein sequence and is enhanced upon the inhibition of mTOR. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, ROS production and the inflammatory response. Consequently, during S. Typhimurium infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to pathogenesis.