Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Developmental Biology

Background:

• Mitochondrial DNA (mtDNA) amount can benefit metabolic stress resistance, but increased mtDNA synthesis is linked to aging.
• The contrasting effects of elevated mtDNA levels necessitate further investigation into mtDNA synthesis regulation.

Purpose of the Study:

• To investigate the consequences of jointly elevating mtDNA amount and replication frequency in mice.
• To elucidate the mechanisms underlying cardiac dysfunction caused by high mtDNA synthesis activity.

Main Methods:

• Generation of mouse models with elevated mtDNA amount and replication frequency.
• Analysis of perinatal cardiac development and function.
• Investigation of molecular pathways including mitochondrial integrated stress response and ferroptosis.

Main Results:

• High mtDNA synthesis activity inhibits perinatal metabolic maturation of the heart.
• Offspring develop dilated cardiomyopathy and cardiac collapse postnatally.
• Pathogenesis involves prenatal upregulation of stress response and MESH1, leading to fibrosis and cardiomyocyte death.
• mtDNA mutagenesis exacerbates the cardiac phenotype.

Conclusions:

• Tight control of mtDNA replication is critical for early cardiac homeostasis.
• Ferroptosis sensitivity represents a potential therapeutic target for infantile-onset cardiomyopathy.
• This study highlights the delicate balance required for mitochondrial function during early development.