Homozygous mutation of UQCR11 leads to mitochondrial dysfunction and severe hypertrophic cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a rare heart disease characterized by left ventricular hypertrophy, often based on genetic causes, typically in sarcomeric genes. However, genetic variants in genes involved in mitochondrial function also contribute to hereditary HCM. In some cases, the respiratory chain complexes are directly affected in either structure or function. This potentially disrupts the electron transport and ATP generation in mitochondria, resulting in energy depletion, especially pronounced in highly energy consuming organs like the heart.

Methods and Results: The 16-year-old female patient from Syria with consanguineous parents presented with concentric HCM progressing into heart failure, requiring heart transplantation at the age of 19 years. Whole exome sequencing identified for the first time a homozygous truncation mutation (p.Y47*) in the mitochondrial respiratory chain complex III (CIII) subunit XI (UQCR11), suggesting a functional knock-out of the protein. UQCR11 is a small 6 kDa subunit of CIII, which stabilizes the catalytic core of CIII and facilitates the binding of co-factors. To gain more insights in the pathogenesis of HCM associated with the loss of UQCR11, we generated cell models mimicking the patient mutation using the CRISPR/Cas9 system, generating a premature stop codon in HeLa cells, resulting in UQCR11-deficient cells which was validated via dot blot. Using UQCR11-deficient HeLa cells, we observed a visually disturbed mitochondrial network in immunofluorescence staining. In Seahorse assays, we could show decreased basal and maximal respiration as well as reduced ATP production when we depleted glycolysis. Additionally, we generated UQCR11-deficient induced pluripotent stem cells (iPS) and iPS-derived cardiomyocytes (iPS-CMs), harboring the same truncation mutation as in HeLa cells, complementing our cellular model of UQCR11-deficient HCM. 

Conclusion und Outlook: We identified a new cause of HCM affecting the respiratory chain complex. UQCR11-deficient HeLa cells show lower basal and maximal oxygen consumption, pinpointing to dysfunctional mitochondria when cells are forced to rely on oxidative phosphorylation. While we started the generation of UQCR11-deficient iPS-CMs, our ongoing studies focus on mitochondrial structure and function as well as the assessment of sarcomere structure, hypertrophy and calcium signaling in cardiomyocytes to generate valuable insights into the impact of UQCR11-deficiency in HCM.