Background:
Mitochondrial dysfunction is implicated in the development of
cardiomyopathy and
heart failure. Transcription of
mitochondrial DNA (
mtDNA) encoded genes and subsequent
protein synthesis are tightly regulated by nuclear
DNA (nDNA) encoded
proteins forming the nDNA-
mtDNA axis. The scale of abnormalities in this axis in
dilated cardiomyopathy (DCM) is unclear. We previously demonstrated, in a mouse DCM model with cardiac Mst1 overexpression, extensive downregulation of mitochondrial genes and
mitochondrial dysfunction. Using the pre-acquired transcriptome sequencing database, we studied expression of gene sets of the nDNA-
mtDNA axis. Methods: Using
RNA-sequencing data from DCM hearts of mice at early and severe disease stages, transcriptome was performed for dysregulated nDNA-encoded gene sets that govern
mtDNA transcription and in situ
protein synthesis. To validate gene data, expression of a panel of
proteins was determined by immunoblotting. Results: Relative to littermate controls, DCM hearts showed significant downregulation of all
mtDNA encoded mRNAs, as well as
mtDNA transcriptional activators. Downregulation was also evident for gene sets of mt-rRNA processing, aminoacyl-
tRNA synthases, and mitoribosome subunits for in situ
protein synthesis. Multiple downregulated genes belong to
mitochondrial protein-importing machinery indicating compromised importing of
proteins for
mtDNA transcription and translation. Diverse changes were genes of
mtRNA-
binding proteins that govern maturation and stability of
mtDNA-derived RNAs. Expression of
mtDNA replicome genes was largely unchanged. These changes were similarly observed in mouse hearts at early and severe stages of DCM. Conclusion: Transcriptome revealed in our DCM model dysregulation of multiple gene sets of the nDNA-
mtDNA axis, that is, expected to interfere with
mtDNA transcription and in situ
protein synthesis. Dysfunction of the nDNA-
mtDNA axis might contribute to
mitochondrial dysfunction and ultimately development of DCM.