Mitochondrial genome linearization is a causative factor for cardiomyopathy in mice and Drosophila.

Chen Y, Sparks M, Bhandari P, Matkovich SJ, Dorn GW.

Aims: Mitofusin (Mfn) 2 redundantly promotes mitochondrial outer membrane tethering and organelle fusion with Mfn1, and uniquely functions as the mitochondrial receptor for Parkin during PINK1-Parkin mediated mitophagy. Selective deletion of Mfn2 with retention of Mfn1 preserves mitochondrial fusion while rendering damaged mitochondria resistant to normal quality control culling mechanisms. Consequently, neuron and cardiomyocyte-specific Mfn2 gene ablation is associated with accumulation of damaged mitochondria and organ dysfunction. Here, we determined how mitochondrial (mt) DNA damage contributes to cardiomyopathy in Mfn2-deficient hearts. Results: RNA sequencing of Mfn2-deficient hearts revealed increased expression of some nuclear-encoded mitochondrial genes, but mitochondrial-encoded transcripts were not upregulated in parallel and mtDNA content was decreased. Ultra-deep sequencing of mtDNA showed no increase in single nucleotide mutations, but copy number variations representing insertion-deletion (in-del) mutations were induced over time by cardiomyocyte-specific Mfn2 deficiency. Double strand mtDNA breaks in the form of in-dels were confirmed by PCR, and in the form of linear mitochondrial genomes were identified by Southern blot analysis. Linearization of Drosophila cardiomyocyte mtDNA using conditional cardiomyocyte-specific expression of mitochondrial targeted XhoI recapitulated the cardiomyopathy of Mfn2-deficient mouse hearts. Innovation: This is the first description of mitochondrial genome linearization as a causative factor in cardiomyopathy. Conclusion: One of the consequences of interrupting mitochondrial culling by the PINK1-Mfn2-Parkin mechanism is an increase in mtDNA double stranded breaks, which adversely impact mitochondrial function and DNA replication.

DNA shearing

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August, 2013



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