The Kidney in Mitochondrial Diseases

Abstract

Mitochondria are small dynamic intracellular organelles with critical roles in energy generation and other aspects of cellular homeostasis. Mitochondrial disorders, which are estimated to have a population prevalence of at least 1 in 4300, are monogenic diseases associated with dysfunction of the oxidative phosphorylation system, mitochondrial ultrastructure and dynamics, production of cofactors and vitamins, or other metabolic processes within the mitochondrion. Renal manifestations are a relatively frequent complication of mitochondrial disease and include Fanconi-type tubulopathy, chronic tubulointerstitial nephritis, steroid-resistant nephrotic syndrome, and cystic glomerular disease. Isolated kidney disease is a rare presentation of mitochondrial disease, although it does occur, particularly in some types of coenzyme Q10 (CoQ10) deficiency. More frequently, renal involvement is part of a complex multisystemic disease. The genetics of mitochondrial disease is complex and includes mutations of the intrinsic mitochondrial DNA (mtDNA) as well as more than 300 nuclear-encoded Mendelian disorders affecting mitochondrial function. The most frequent causes of mitochondrial nephropathy are point mutations and large-scale rearrangements of the mtDNA and autosomal recessive disorders of CoQ10 biosynthesis. Increasingly, exome and genome sequencing of large cohorts is leading to the identification of novel genetic causes of mitochondrial kidney disease, including disorders of mtDNA maintenance, mitochondrial translation, mitochondrial dynamics, and biosynthesis of membrane lipids and iron-sulfur clusters. Diagnosis is challenging, as there may be few clues from renal or muscle biopsy and biochemical testing, and the approach to diagnosis increasingly involves genome-wide next generation sequencing.