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

Yun Chen, Megan Sparks, Poonam Bhandari, Scot J. Matkovich, Gerald W. Dorn

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 PTEN-induced putative kinase 1 (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 DNA (mtDNA) 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 polymerase chain reaction, 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. Antioxid. Redox Signal. 21, 1949-1959.

Original languageEnglish (US)
Pages (from-to)1949-1959
Number of pages11
JournalAntioxidants and Redox Signaling
Volume21
Issue number14
DOIs
StatePublished - Nov 10 2014
Externally publishedYes

Fingerprint

Mitochondrial Genome
Cardiomyopathies
Mitochondrial DNA
Linearization
Drosophila
Genes
Cardiac Myocytes
Mitochondria
Fusion reactions
Mitochondrial Degradation
INDEL Mutation
Mitochondrial Dynamics
RNA Sequence Analysis
Polymerase chain reaction
High-Throughput Nucleotide Sequencing
Ablation
Mitochondrial Genes
Double-Stranded DNA Breaks
Mitochondrial Membranes
Neurons

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry
  • Medicine(all)

Cite this

Mitochondrial genome linearization is a causative factor for cardiomyopathy in Mice and Drosophila. / Chen, Yun; Sparks, Megan; Bhandari, Poonam; Matkovich, Scot J.; Dorn, Gerald W.

In: Antioxidants and Redox Signaling, Vol. 21, No. 14, 10.11.2014, p. 1949-1959.

Research output: Contribution to journalArticle

Chen, Yun ; Sparks, Megan ; Bhandari, Poonam ; Matkovich, Scot J. ; Dorn, Gerald W. / Mitochondrial genome linearization is a causative factor for cardiomyopathy in Mice and Drosophila. In: Antioxidants and Redox Signaling. 2014 ; Vol. 21, No. 14. pp. 1949-1959.
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