An international study, the result of collaboration between the National Center for Cardiovascular Research Carlos III (CNIC) and the University of California, Los Angeles (UCLA), has revealed an essential mechanism that governs how the body uses stored fat to generate energy.
The findings, published in "The EMBO Journal," detail that calcium present within mitochondria acts as a signal that decides whether these organelles remain attached or detach from lipid droplets, structures where cells store fat.
Mitochondria are the organelles responsible for producing most of the energy needed for tissues to function correctly. In brown adipose tissue, a type of fat specialized in producing heat and increasing energy expenditure, a fraction of mitochondria remain physically attached to lipid droplets, forming so-called peridropletal mitochondria. These mitochondria are crucial for managing the cell's energy reserves.
The research, whose first author is Rebeca Acín-Pérez, a scientist at CNIC and the Center for Biomedical Research Network on Frailty and Healthy Aging, demonstrates that increased calcium levels inside mitochondria induce changes in their shape and promote their separation from lipid droplets. "This process is essential for the enzymes responsible for fat breakdown, known as lipases, to access stored lipids and convert them into energy," assures Acín-Pérez.
The team also found that this disconnection of mitochondria occurs before lipolysis begins, acting as a kind of molecular switch that activates the mobilization of fat reserves.
The study also identifies the proteins involved in this control. In particular, the mitochondrial calcium exchanger NCLX regulates the exit of calcium from mitochondria. When NCLX activity is reduced, more calcium accumulates inside mitochondria, the separation of mitochondria from lipid droplets is enhanced, and the use of fat as an energy source increases. Conversely, when NCLX remains active, mitochondria tend to stay associated with lipid deposits.
Scientists also describe a prominent role for the phosphodiesterase PDE2A, a protein that indirectly modulates this circuit by influencing intracellular calcium levels.
Beyond characterizing this biological process, the work demonstrates that its manipulation through drugs can have relevant metabolic effects. In animal models of obesity, blocking PDE2A increased the binding between mitochondria and lipid droplets, decreased fat degradation, and promoted the conversion of glucose into the main energy fuel. This metabolic readjustment was related to an improvement in energy control and an increase in metabolic expenditure.
Overall, the data highlight that the relationship between mitochondria and lipid droplets is dynamic and finely orchestrated by internal signals such as calcium. "Understanding how this relationship is controlled provides a new perspective on the mechanisms that regulate energy metabolism and opens possible avenues for the development of therapeutic strategies for obesity and other metabolic diseases," the authors state.
The study is part of the collaboration between the group led by José Antonio Enríquez, head of the Functional Genetics of Oxidative Phosphorylation System Group at the CNIC, and the team of Orian Shirihai at the David Geffen School of Medicine at UCLA (USA), a cooperation that in recent years has deepened the understanding of mitochondrial function and its impact on metabolism regulation.