Mitochondrial DNA errors impaired cardiac function in mice and were accompanied by immune remodeling of the tissue

Mitochondrial DNA errors impaired cardiac function in mice and were accompanied by immune remodeling of the tissue

On 4 September, a Science Advances article described a mouse model in which errors accumulated in the mitochondrial DNA of cardiomyocytes, the cells that contract the heart. By nine months, the animals had reduced activity of the energy-producing respiratory chain and weaker cardiac contractions. Collagen deposits and immune cells appeared in aging hearts.

Mitochondria supply cells with energy and contain their own DNA. This DNA is copied by POLG, a protein that corrects some errors during replication. In an earlier mouse line, a POLG variant with impaired proofreading was active throughout the body. Cardiac disease therefore reflected both changes within cardiomyocytes and the condition of other tissues.

The authors created a version of the Polg gene that could be activated in cardiomyocytes. After activation, the cells produced the POLG D257A variant, which has impaired DNA replication proofreading. This construct allowed the researchers to trace the effects of mutations that had accumulated specifically in heart cells. At nine months, the mitochondrial DNA mutation burden in the heart was approximately half that of mice with altered POLG throughout the body, while body and organ mass remained normal.

In nine-month-old animals, the activity of respiratory chain complexes I and IV decreased by approximately one-quarter. Fractional shortening, the proportion by which the left ventricle contracts with each heartbeat, decreased by approximately the same amount. Contractile function declined before any substantial remodeling of the cardiac chambers and walls became apparent.

By 12–16 months, cardiac contractions had weakened further. By 16 months, the mutation burden had reached the level found in nine-month-old mice with altered POLG throughout the body. Tissue sections from these hearts showed focal collagen deposits, indicating the growth of connective tissue. The loss of respiratory chain components varied among hearts and among regions within the same tissue.

Hearts with a higher mutation burden and lower levels of respiratory chain proteins showed stronger interferon signaling and greater activity of the system through which cells present protein fragments to the immune system. These hearts also contained more immune cells, particularly dendritic cells. Microscopy showed these cells between cardiomyocytes. These findings link severe respiratory chain dysfunction to immune remodeling of the heart.

This model separates the effects of mitochondrial DNA errors within cardiomyocytes from those caused by disease affecting the whole body. It can be used to test which signals from damaged heart cells recruit immune cells.