Uqcrh – a new player in mitochondrial complex III disorders

Source: GMC

This translational study recently published in EMBO Molecular Medicine sheds light on the UQCRH gene and mitochondrial complex III diseases. An international team led by researchers and clinicians from Helmholtz Zentrum München, Germany, Manchester Centre for Genomic Medicine, UK, Newcastle University, UK and University Hospital Salzburg, Austria, identified two cousins with a deletion in the UQCRH gene, which codes for a structural complex III subunit, and characterized a novel mouse model that carries the equivalent deletion in Uqcrh. The characteristics and biochemical similarities of the Uqcrh-/- mouse model suggest that this could be a valuable system to study the biology of human diseases caused by CIII defects.

Mitochondrial diseases are a group of complex genetic disorders that in most cases result in energy production deficiency. Mitochondrial dysfunction may result in oxidative chain defects and subsequent pathological development. The clinical presentations are heterogeneous, mostly affecting tissues with high-energy requirements. Isolated respiratory chain complex III (CIII) deficiencies are rare and begin in the childhood. Most medical care is only intended to relieve symptoms.

This study documents the first cases of mitochondrial disease due to variants in UQCRH, a mitochondrial protein encoded by the nuclear genome and a subunit of complex III, one of 5 multi-subunit complexes that make up the OXPHOS system. The scientists describe two affected cousins who presented with episodes of metabolic crisis, manifested itself as severe lactic acidosis, high ammonia levels, low glucose levels and brain abnormalities. Whole exome sequencing identified a 2.2 kb dropout of sequencing reads predicting a homozygous deletion of two out of the four coding regions of the gene. The mouse model that carries the same deletion showed similar symptoms of lactic acidosis and high ammonia levels, and interestingly initial hypoglycemia that developed in diabetes. Biochemically, skin fibroblasts from the affected children and tissues of the mouse model lack UQCRH/Uqcrh protein expression, showed an impaired complex III activity, and reduced size of assembled complex III. Moreover, complex profiling revealed that the absence of UQCRH did not affect the ability of complex III to dimerize neither to form large OXPHOS supercomplexes.

The confirmation of this variant as causative enables pre-symptomatic accurate diagnosis of at risk individuals in the family, demonstrating the clinical importance of providing a genetic diagnosis in mitochondrial disease cases. The similarities in the biochemical analyses of the patient fibroblasts and Uqcrh-/- mouse tissue suggest that the Uqcrh-/- mouse model could be a valuable system to study the biology of human diseases caused by CIII defects. In addition, the disease model can support the development of new and more effective therapeutic strategies targeting CIII defects or related mitochondrial disorders.

Vidali S, Gerlini R, Thompson K, Urquhart JE, Meisterknecht J, Aguilar-Pimentel JA, Amarie OV, Becker L, Breen C, Calzada-Wack J, Chhabra NF, Cho YL, da Silva-Buttkus P, Feichtinger RG, Gampe K, Garrett L, Hoefig KP, Hölter SM, Jameson E, Klein-Rodewald T, Leuchtenberger S, Marschall S, Mayer-Kuckuk P, Miller G, Oestereicher MA, Pfannes K, Rathkolb B, Rozman J, Sanders C, Spielmann N, Stoeger C, Szibor M, Treise I, Walter JH, Wurst W, Mayr JA, Fuchs H, Gärtner U, Wittig I, Taylor RW, Newman WG, Prokisch H, Gailus-Durner V, Hrabě de Angelis M. Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes. EMBO Mol Med. 2021 Nov 8:e14397. PMID: 34750991.