Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM

Abstract

The mitochondria of the proximal tubule are essential for providing energy in this nephron segment, whose ATP generation is almost exclusively oxygen dependent. In addition, mitochondria are involved in a variety of metabolic processes and complex signaling networks. Proximal tubular mitochondrial dysfunction can therefore affect renal function in very different ways. Two autosomal dominantly inherited forms of renal Fanconi syndrome illustrate how multifaceted mitochondrial pathology can be: Mutation of EHHADH, an enzyme in fatty acid metabolism, results in decreased ATP synthesis and a consecutive transport defect. In contrast, mutations of GATM, an enzyme in the creatine biosynthetic pathway, leave ATP synthesis unaffected but do lead to mitochondrial protein aggregates, inflammasome activation, and renal fibrosis with progressive renal failure. In this review article, the distinct pathophysiological mechanisms of these two diseases are presented, which are examples of the spectrum of proximal tubular mitochondrial diseases.

A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end‐stage kidney disease

“…Of note, mice haploinsufficient for GATM had no significant kidney phenotype, suggesting the four variants cause disease through a dominant negative mechanism. These mice did however display neurological phenotypes consistent with biallelic loss‐of‐function variants in GATM 8 . Of interest, rats treated with oral creatine showed 27% reduced kidney GATM expression and 58% reduced protein levels.…”

“…These mice did however display neurological phenotypes consistent with biallelic loss-of-function variants in GATM. 8 Of interest, rats treated with oral creatine showed 27% reduced kidney GATM expression and 58% reduced protein levels.…”

“…GATM encodes a proximal tubular nuclear‐encoded mitochondrial enzyme, glycine amidinotransferase, which catalyses the transfer of a guanidino group from l ‐arginine to glycine, resulting in guanidinoacetic acid, an immediate precursor to creatine 8 . GATM is most prominently expressed in kidney, liver, pancreas, and brain.…”

“…GATM encodes a proximal tubular nuclear‐encoded mitochondrial enzyme, glycine amidinotransferase, which catalyses the transfer of a guanidino group from l ‐arginine to glycine, resulting in guanidinoacetic acid, an immediate precursor to creatine. 8 GATM is most prominently expressed in kidney, liver, pancreas, and brain. In the kidney, GATM expression is limited to the highly energy dependent proximal tubular cells, which have abundant mitochondria to support the oxygen‐dependent generation of ATP.…”

“…These mice did however display neurological phenotypes consistent with biallelic loss‐of‐function variants in GATM . 8 Of interest, rats treated with oral creatine showed 27% reduced kidney GATM expression and 58% reduced protein levels. Therefore, exogenous creatine may suppress endogenous production of mutant GATM and reduce production of abnormal protein aggregates.…”