HMN 2026: How RHOT proteins regulate energy supply in heart muscle cells

Our hearts beat around 100,000 times a day—and do so throughout our entire lives. They draw the energy for this from the mitochondria. As the “powerhouses of the cells,” mitochondria produce 95% of adenosine triphosphate (ATP), the body’s most important energy currency. If the mitochondria are impaired and cannot function properly, the heart muscle cells lack the strength to pump sufficient blood, oxygen, and nutrients into the body.

Due to its high energy requirements, the heart has the highest mitochondrial density of all organs, accounting for around a third of its cell volume. During heart development, the mitochondria migrate to the so-called sarcomeres. These smallest components of the muscle cell enable contraction and require energy to do so.

Researchers led by Dr. Christian Riehle—head of the Myocardial Energetics research group at the Department of Cardiology and Angiology at Hannover Medical School (MHH)—and Clinic Director Prof. Dr. Johann Bauersachs have demonstrated that the movement of mitochondria within heart muscle cells is controlled by so-called RHOT proteins. This process plays a key role when the heart grows and is under particular strain. This may occur during competitive sports, and also during disease-related remodeling processes in the heart muscle, such as following a heart attack.

RHOT proteins therefore represent a promising new approach for the treatment of heart failure. The results of the team’s study have been published in the journal Circulation Research.

Without RHOT, the heart cannot develop

The research team discovered the proteins through a bioinformatic gene analysis.

“We saw that a great deal of RHOT1 and RHOT2 is produced in the heart,” says PD Dr. Riehle. Until then, the function of the proteins in the heart had been largely unknown. “However, their high abundance was a clear indication to us that they must be responsible for a key mechanism,” he adds.

The researchers then investigated the biological signaling pathway in a mouse model.

“We knocked out the two proteins, RHOT1 and RHOT2, in the heart muscle cells during embryonic development,” explains Dr. Natali Froese, a research associate in the group and first author of the study. “As a result, the mitochondria did not migrate to the sarcomeres but instead clustered around the cell nucleus.”

Because the mitochondria could no longer bind to the muscle fiber proteins, the sarcomeres lacked the energy for their further development, leading to heart weakness and heart failure.

Important even under increased workload

The researchers also knocked out RHOT1 and RHOT2 in adult mice. Here, however, the loss of these molecular switches did not have the same fatal effect. Although mitochondrial mobility was equally restricted, ATP production at the sarcomeres was maintained.

“This means that in mature heart muscle cells, the mitochondria are already at their intended location,” explains Dr. Riehle. The migration towards the sarcomeres therefore takes place during embryonic development.

The second finding from the study is that RHOT proteins may also play an important role when the heart is under increased workload—for example, following a heart attack, when dead heart muscle tissue is replaced by non-functional connective tissue and the remaining heart muscle cells must compensate for the loss.

“In this context, RHOT proteins represent an attractive therapeutic target,” explains PD Dr. Riehle.

One possibility would be to increase the activity of the RHOT proteins so that more energy is available to the heart muscle cells. A gene therapy approach would be conceivable here.

Possible treatment approach for PPCM

The heart muscle cells are also subjected to greater strain during pregnancy. The heart muscle enlarges by up to 30%. This is completely normal, but in exceptional cases it can lead to life-threatening peripartum cardiomyopathy (PPCM). This condition can occur in women with previously healthy hearts a few weeks before or after the birth of a child and can lead to severe heart failure and even death within a short period of time.

“Our clinic is Europe’s leading PPCM center with a specialist outpatient clinic that cares for patients through a multi-disciplinary team,” emphasizes Professor Bauersachs.

The condition is not only treated at the clinic, but is also one of its key research areas.

“The RHOT proteins could also offer a therapeutic approach here to relieve the strain on the heart muscle cells of pregnant women and protect the heart,” says the clinic director.

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