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Microproteins Control Molecular-Level Metabolic Processes

Researchers at Duke-NUS Medical School have uncovered how microproteins play a role in regulating the energy supply in mitochondria.

Researchers at Duke-NUS Medical School have identified new details regarding how cells regulate their energy supply to meet energy demand. Their study was produced in partnership with researchers at the University of Melbourne in Australia and Duke University in Durham, North Carolina, USA, and details the key role that microproteins play during the production of protein complexes in mitochondria, commonly known as the powerhouse of the cell.

Mitochondrial problems are often responsible for a large variety of common diseases, like cancer, diabetes, heart failure, and obesity.

“Our long-term goal is to learn how to manipulate the microproteins we are investigating to combat mitochondrial dysfunction in patients,” said senior author Assistant Professor Lena Ho, from Duke-NUS’s Cardiovascular & Metabolic Disorders (CVMD) Programme. She also highlights that the greatest and most immediate significance of her team’s research is that it demystifies mitochondria function and maintenance in all cells, allowing for a better understanding of a key focus in cell biology.

Mitochondria, the energy-producing centres of the cell, have double membranes, of which the inner membrane is embedded with a multitude of proteins that transfer electrons along the electron transport chain. The electron transport chain is a key step in oxidative phosphorylation, which produces adenosine triphosphate (ATP), an essential energy-carrying molecule.

The Duke-NUS team also discovered that peptides, which may be thought of as smaller microproteins, have an unprecedented role in the formation of the electron transport chain. In particular, they synergise to mutually aid and control the assembly of a central protein in the electron transport chain, commonly known as Complex III. Hence, these microproteins are involved in the regulation of the electron transport chain proteins that control the overall energy supply.

“Mitochondria are the batteries and factories of our cells, making not only energy but also many of the building blocks required for cells to multiply and stay alive,” said Dr. Shan Zhang, a former research fellow with Asst Prof Ho’s Endogenous Peptides Lab, under Duke-NUS’ CVMD Programme, and now an Assistant Professor at Zhejiang University, China. He also noted that regulating microprotein levels might reduce the incidence of mitochondrial dysfunction, which may help offer protection or treatment for common metabolic diseases.

In further research, the team hopes to be able to examine the roles and the importance of the microproteins at a closer level, starting with preclinical models, before moving on to humans. Asst Prof Ho hopes that further research will allow her team to develop treatments for mitochondrial diseases with microprotein levels as the key therapeutic target. [APBN]

Source: Liang et al. (2022). Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis. Cell Reports, 40(7), 111204.