Loss of Mitochondrial Transcription Factor A (TFAM) in Tubule Cells Causes Renal Failure Via Activating the cGAS-STING Innate Immune Pathway

Kidney fibrosis is characterized by tubule atrophy, compromised bioenergetics and proinflammatory gene expression. The relationship between these events are poorly understood. In patient samples, the expression of TFAM and mitochondrial genes correlates with kidney fibrosis. Mice with tubule specific deletion of TFAM (Ksp-Cre/Tfam flox/flox) developed severe mitochondrial loss and decline of ATP content by 6 weeks of age. Progressive azotemia, kidney fibrosis and death of the animals was only observed after 12 weeks of age. Mechanistic studies demonstrated that aberrant mtDNA packaging upon TFAM deficiency in tubule cells resulted in escape of mtDNA into the cytosol, activation of the cytosolic DNA sensing pathway, the Stimulator of interferon genes (STING), resulting in cytokine expression and immune cell recruitment. Genetic deletion or pharmacological inhibition of STING ameliorated TFAM-loss induced kidney fibrosis, demonstrating, that in addition to its essential role in metabolism, TFAM sequesters mtDNA to prevent the activation of innate immune pathways and fibrosis.