Mitochondrial haplotype modulates genome expression and mitochondrial structure/function in cardiomyocytes following...

Area of Science:

• Cardiovascular Biology
• Mitochondrial Genetics
• Molecular Cardiology

Background:

• Mitochondrial DNA (mtDNA) haplotype influences cellular function and disease susceptibility.
• Aortocaval fistula (ACF) in mice models volume overload, impacting cardiac function.
• Understanding mtDNA haplotype effects on cardiomyocyte response to ACF is crucial for potential therapeutic strategies.

Purpose of the Study:

• To investigate the impact of different mtDNA haplotypes on cardiomyocyte ultrastructure and gene expression in response to ACF.
• To elucidate the role of mitochondrial-nuclear genome interactions in cardiac adaptation to ACF.

Main Methods:

• Utilized wild-type (C57BL/6J and C3H/HeN) and mitochondrial nuclear exchange (MNX) mice models.
• Performed quantitative transmission electron microscopy (TEM) to assess cardiomyocyte mitochondrial ultrastructure.
• Conducted RNA sequencing to analyze cardiomyocyte transcriptome response to sham surgery or ACF.

Main Results:

• C3H wild-type hearts exhibited more compact mitochondrial cristae compared to C57 wild-type.
• ACF induced mitochondrial swelling and disorganization in C57 wild-type and MNX hearts, but not in C3H wild-type.
• C3H wild-type hearts showed increased autophagy and antioxidant gene expression, while C57mtDNA was linked to inflammatory pathways and reduced bioenergetics.

Conclusions:

• The C3H mtDNA haplotype confers a protective response against ACF-induced cardiac stress, mediated by mitochondrial-nuclear genome interactions.
• mtDNA haplotype significantly influences nuclear gene expression in cardiomyocytes, impacting pathways involved in stress response and energy metabolism.
• These findings highlight the potential of targeting mtDNA-related pathways for managing heart conditions associated with volume overload.