Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA146

Poster Communications

Mitochondrial aggregates of mutated glycine amidinotransferase (GATM) cause renal Fanconi syndrome and kidney failure.

R. Warth1, M. Reichold1, E. Klootwijk2, J. Reinders3, E. Otto4, M. Milani5, W. Gahl6, R. Unwin2, R. Kleta2

1. Medical Cell Biology, Universität Regensburg, Regensburg, Germany. 2. Royal Free Hospital, Centre for Nephrology, UCL, London, United Kingdom. 3. Institut für Funktionelle Genomik, Universität Regensburg, Regensburg, Germany. 4. Division of Nephrology, University of Michigan, Ann Arbor, MI, USA., Ann Arbor, Michigan, United States. 5. CNR-Biophysics Institute, Milan, Italy, Milan, Italy. 6. NHGRI, NIH, Bethesda, Maryland, United States.


Chronic kidney disease (CKD) affects 8-16% of the adult population. A histological hallmark of CKD is renal fibrosis, a process correlating with the progressive decline of kidney function. The pathophysiology of renal fibrosis is complex and often involves the release of profibrotic and inflammatory signals from damaged tubular cells. Here, we investigated the patho-mechanism of a novel form of hereditary renal Fanconi syndrome with kidney failure. Members of five families with autosomal dominant renal Fanconi syndrome and kidney failure were clinically and genetically characterized. We performed genome-wide linkage analysis and DNA sequencing as well as immuno-localization studies, evaluation of mitochondrial morphology and cell biology assays. Structural studies examined the effects of recognized mutations. In all our patients, novel mutations in the "glycine amidinotransferase" (GATM) gene, a renal proximal tubular enzyme in the creatine biosynthetic pathway, were identified. Mutant GATM proteins form fibrillary aggregates in mitochondria triggering an inflammasome response and profibrotic signals. All heterozygous missense mutations were located within the non-catalytic domain of GATM. Gatm knockout mice showed no renal abnormalities, rendering haploinsufficiency unlikely. Unexpectedly, proximal tubular cells expressing mutated GATM and patients' kidney biopsies showed massively enlarged mitochondria with fibrillary aggregates containing GATM. In fact, structure analysis predicted an additional interaction interface for mutated GATM enabling linear aggregation of GATM dimers. Once aggregated, GATM fibrils escaped degradation and resulted in aging of mitochondria. Aggregates-containing mitochondria were associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18 and increased cell death. These data establish a link between pathological intramitochondrial GATM protein deposits, inflammation and kidney fibrosis.

Where applicable, experiments conform with Society ethical requirements