Mitochondrial protein contributes to degenerative diseases

Scientists and their collaborators from Duke-NUS Medical School (Duke NUS) have recently identified a novel small protein in mitochondria, which is essential for energy production. The team has reported this finding in the Nature Communications journal.

Zebrafish

Image Credit: peter verreussel/Shutterstock.com

Zebrafish that lacked this small protein, dubbed BRAWNIN by the researchers, were found to have features that were similar to the rare mitochondrial diseases in humans.

This suggested that additional studies of the protein might help explain these rare conditions and discover potential treatments.

The international team of researchers, headed by Lena Ho, a cell and developmental biologist and an Assistant Professor at Duke-NUS Medical School’s Cardiovascular and Metabolic Disorders Programme, has successfully identified 16 “short open reading frame-encoded peptides” (SEPs).

The genetic code of these SEPs is first translated into the nucleus and then imported into mitochondria, which are the power-generating structures of cells.

SEPs have been fascinating the scientific community for several years now, as they represent a mini-proteome that has never been explored; a repository of new gene functions. But there haven’t been systematic studies to validate their functions and biological relevance. We found that the mitochondria are a hotspot for their functions, for reasons we don’t completely yet understand.”

Lena Ho, Assistant Professor, Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School

The researchers extracted one of the 16 mitochondrial SEPs, which they had discovered for additional analysis. When the scientists knocked out the gene that coded for the mitochondrial SEP, that is, the BRAWNIN, in the zebrafish, they observed severe growth retardation as well as accumulation of lactic acid in cells.

Additional tests demonstrated that BRAWNIN was crucial for the assembly of a cluster of molecules in mitochondria known as respiratory chain complex III. According to Dr. Ho, this molecular complex was vital for all forms of life that utilize oxygen for generating energy.

At present, the researchers are trying to figure out the actual role BRAWNIN of in the complex III assembly.

They are also exploring the types of diseases that could be susceptible to BRAWNIN malfunction and whether the protein could be used as a potential target to reverse their pathologies.

Mitochondrial decline and dysfunction underlies all degenerative diseases and has been widely implicated in cancer. The proteins we’ve discovered, including BRAWNIN, represent potential targets for reversing mitochondrial decline.”

Lena Ho, Assistant Professor, Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School

According to Professor Patrick Casey, the Senior Vice Dean for Research at Duke-NUS Medical School, “Degenerative diseases and cancer are major health concerns in Singapore and around the globe. The insights gained from Asst Prof Ho’s study reaffirms the value of our commitment to fundamental scientific research that can potentially help solve some of these problems.”

Dr. Ho also observed that 15 more mitochondrial SEPs are available for investigation.

We are actively looking for collaborators who are interested in studying them.”

Lena Ho, Assistant Professor, Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School

Source:
Journal reference:

Zhang, S., et al. (2020) Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Nature Communications. doi.org/10.1038/s41467-020-14999-2.

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