A novel form of autosomal dominant tubuloglomerular disease is caused by mutations in the GATM gene that result in mitochondrial abnormalities, say Robert Kleta and colleagues. GATM encodes the mitochondrial enzyme glycine amidinotransferase (GATM), which has a role in creatine biosynthesis.

Using genome-wide linkage analysis and sequencing studies, the researchers identified four heterozygous missense mutations in GATM in 28 patients with Fanconi syndrome and kidney failure from five extended families. Kidney biopsy samples from these patients showed fibrosis and proximal tubule cells with extremely large mitochondria that contained pathological GATM aggregates. Overexpression of mutant GATM in a proximal tubule cell line resulted in a similar mitochondrial phenotype, whereas proximal tubule cells that expressed wild-type GATM had normal mitochondrial morphology.

To investigate the effect of the disease-causing GATM mutations on the protein, the researchers performed in silico analyses. They report that these mutations result in the formation of an interaction site that could enable GATM to form linear multimers consistent with the mitochondrial aggregates.

Finally, the researchers show that overexpression of mutant GATM in proximal tubule cells impaired mitochondrial turnover and led to increased production of reactive oxygen species, initiation of an inflammatory response, release of profibrotic factors and increased cell death.

“We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis,” conclude the researchers. “The disease also illustrates the critical role that mitochondria can play in initiating devastating profibrotic signalling cascades.”