Mutations in mitochondrial DNA (mtDNA) and mitochondrial dysfunction have been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Now, Jeremy Duffield and colleagues report that in mice, a loss-of-function mutation in the Cox10 gene, which encodes a cofactor for complex IV of the electron transport chain, results in activation of the innate immune system and the development of FSGS.

“Mitochondria are a vestige of a symbiosis between eukaryotic cells and prokaryotic cells, so the mitochondria are hiding in plain sight from the intracellular innate immune sensing system,” explains Duffield. “We were interested in investigating whether dysfunctional mitochondria can activate the intracellular immune response.”

To answer this question, the researchers generated mice with nephron-specific knockout of Cox10. They report that these mice develop a severe, early-onset form of FSGS with tubulointerstitial damage, fibrosis, inflammation and premature death due to kidney failure.

“We found evidence that not only does Cox10 silencing result in partial loss of mitochondrial function, but also that it results in activation of the intracellular sensing system for foreign or viral DNA,” says Duffield. Additional experiments suggested that loss of Cox10 in kidney epithelial cells leads to leakage of mtDNA into the cytosol and activation of the DNA sensor STING, resulting in the induction of an interferon response and activation of the innate immune system.

The researchers conclude that loss of COX10 is sufficient to cause severe FSGS. In addition, they hypothesize that the release of mtDNA may be a novel mechanism that contributes to the pathogenesis of FSGS in the setting of mitochondrial dysfunction.