New study reveals key role of mitochondrial proteins in heart regeneration

Mitochondria play a critical role in providing the energy necessary for the proper functioning of cells. In mitochondria, energy is produced by the respiratory chain, which consists of five complexes called CI-CV. These complexes can assemble into supercomplexes, but little is known about the role of this process and its control.

New research examines the mechanisms of supercomplex assembly and reveals the significant influence of mitochondrial assembly factors on cardiac tissue regeneration. The study was co-led by Dr. José Antonio Henriques of the National Center for Cardiovascular Research (CNIC) and Dr. Nadia Mercader of the University of Bern in Switzerland, who is a visiting scientist at the CNIC.

Research published in the journal Developmental Cell shows that member of the Cox7a family of proteins plays a fundamental role in the assembly of CIV dimers and that this assembly is critical for proper mitochondrial function and therefore for the production of cellular energy.

The Cox7a family of proteins includes three members: Cox7a1, Cox7a2, and Cox7a2l (also called SCAF1). Previous studies from both groups have shown that when CIV contains SCAF1, it associates strongly with CIII, forming a respiratory supercomplex known as the respirasome. In these previous studies, the authors hypothesized that inclusion of Cox7a2 would result in the formation of association-incompetent CIV, while CIV molecules containing Cox7a1 would associate to form CIV homodimers. A new study experimentally demonstrates the role of Cox7a1 in the formation of these CIV homodimers.

Developmental Cell (2024). DOI: 10.1016/j.devcel.2024.04.012

Working in a zebrafish model, the researchers found that the absence of Cox7a1 prevented the formation of CIV dimers, and the loss of these dimers affected the weight and swimming ability of affected fish.

“Cox7a1 is primarily expressed in striated muscle cells, and it was skeletal muscle tissue that was most affected by the lack of Cox7a1 function. The other main type of striated muscle is the heart muscle, or myocardium,” Dr. Enriquez explained.

However, while loss of Cox7a1 in skeletal muscle was deleterious, its absence in cardiac muscle improved the heart's regenerative response to injury.

“This result shows that these proteins play a key role in activating the heart's ability to repair itself after injury,” explained study first author Carolina Garcia-Poyatos.

To further understand the function of Cox7a1, CNIC researchers Enrique Calvo and Jesus Vazquez conducted a proteomic study of the skeletal muscle and myocardium of zebrafish lacking Cox7a1. This analysis was extended by a metabolomics study carried out by colleagues at the University of Bern. This joint analysis revealed significant differences from unmodified fish with intact Cox7a1 expression.

“These results suggest that molecules involved in the assembly of mitochondrial supercomplexes may have significant effects on metabolic control, perhaps opening the way to new treatments for heart disease and other metabolic conditions,” Dr. Mercader said.

According to the research team, this discovery represents "a significant advance in understanding the cellular mechanisms involved in cardiac regeneration and may point the way to the development of therapies aimed at promoting cardiac regeneration."

The authors conclude that mitochondrial assembly factors may significantly influence metabolic control.