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iPSCs and CRISPR/Cas9 Combine to Faithfully Model CoQ10 Deficiency

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Review of “Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency” from STEM CELLS by Stuart P. Atkinson

The exciting combination of patient-specific Induced pluripotent stem cell (iPSC) generation combined with CRISPR/Cas9 gene editing is fast becoming the ideal means to model human disease and devise possible treatment strategies. An new STEM CELLS study from the laboratory of Pablo Menendez (University of Barcelona, Spain) [1] has applied these synergistic technologies to primary Coenzyme Q10 (CoQ10) deficiency; a rare mitochondrial disorder [2] caused by a mutation in the COQ4 gene [3].

Unfortunately, CoQ10 deficiency impairs oxidative phosphorylation and global metabolic homeostasis, and therefore negatively affects tissues with high-energy demands, such as the brain and skeletal muscle. We currently lack the pharmacological means to treat these pathologies, but can iPSC and CRISPR/Cas9 technologies come together to tell us more about this rare but serious disorder?

The generation of iPSCs in this new study employed Sendai virus-based reprogramming of fibroblasts derived from a COQ4 mutation-carrying patient who had displayed minor mental retardation and lethal rhabdomyolysis, a condition in which damaged skeletal muscle breaks down rapidly (See figure: muscle histology revealing mitochondrial alterations after rhabdomyolysis). The fibroblasts themselves presented with low levels of CoQ10 and CoQ10 biosynthesis and exhibited mitochondrial and metabolic deficits.

Once generated, the authors corrected the COQ4 mutation via CRISPR/Cas9 gene editing to create an “isogenic” control iPSC line for side-by-side comparisons that confirmed that the COQ4 mutation led to CoQ10 deficiency and metabolic/mitochondrial dysfunction. Assessment of iPSC differentiation potential suggested that iPSCs successfully recapitulated the patient’s disease phenotype, as the COQ4 mutation impaired skeletal muscle differentiation of iPSCs and any skeletal muscle produced displayed metabolic defects. However, the COQ10 mutation did not alter differentiation into dopaminergic or motor neurons, which perhaps reflects the minor mental retardation observed in the patient.

Overall, the faithful reproduction of skeletal muscle dysfunction in COQ4 iPSCs suggests that these pluripotent cell types may prove useful in the search for new drugs to treat CoQ10 deficiency. Furthermore, the efficient and effective correction of COQ4 iPSCs by CRISPR/Cas9 gene editing may also provide cell-based therapies that will work hand in hand with pharmacological strategies.

Stay tuned to the Stem Cells Portal to discover more on what iPSCs and CRISPR/Cas9 can do for your research! 

References

  1. Romero-Moya D, Santos-Ocaña C, Castaño J, et al. Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency. STEM CELLS 2017;35:1687-1703.
  2. Quinzii CM and Hirano M. Primary and secondary CoQ(10) deficiencies in humans. BioFactors 2011;37:361-365.
  3. Casarin A, Jimenez-Ortega JC, Trevisson E, et al. Functional characterization of human COQ4, a gene required for Coenzyme Q10 biosynthesis. Biochem Biophys Res Commun 2008;372:35-39.