Hidden Role of Biliverdin Reductase A in Fighting Oxidative Damage

According to a new study from Johns Hopkins Medicine, the enzyme biliverdin reductase A (BVRA) protects neurons directly from oxidative stress, regardless of whether it produces the yellow pigment bilirubin. The study was published in Proceedings of the National Academy of Sciences.

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By modifying another important enzyme, NRF2, which controls the levels of protective proteins and antioxidants in cells, BVRA shielded brain cells from oxidative stress, an imbalance between oxidants and antioxidants that can harm cells, according to this study of genetically modified mice. Alzheimer's disease and other neurodegenerative disorders are characterized by oxidative stress.

Our research identifies BVRA as a key player in cellular defense with profound implications for aging, cognition and neurodegeneration.

Bindu Paul, M.S., Ph.D., Study Lead, Associate Professor, Pharmacology, Psychiatry and Neuroscience, Johns Hopkins University School of Medicine

“This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer’s disease,” added Solomon H. Snyder, M.D., co-corresponding author.

The current study expands on previous NIH-funded Johns Hopkins research, which demonstrated how bilirubin acts as an antioxidant in mice's brains. More recently, a study showed that the pigment protects mice from the deadliest consequences of malaria.

In a new study, scientists genetically engineered mice to lack genes that produce both BVRA and NRF2 proteins. However, none of these mice survived, suggesting that these proteins may have a significant relationship.

Next, in mice genetically engineered to lack just BVRA, the scientists discovered that NRF2 malfunctioned and its target genes generated fewer antioxidants. In cell cultures, scientists demonstrated that BVRA and NRF2 physically bind and, as a result, control genes that protect brain cells. Both proteins control genes involved in oxygen transport, immunological signaling, and the optimal operation of mitochondria, the cell's powerhouse.

Importantly, this activity does not require BVRA to generate bilirubin. The scientists then created BVRA mutants that were unable to produce bilirubin. The scientists suggested that these mutants preserved their capacity to control NRF2 and protect neurons in mice.

This work shows that BVRA does more than produce bilirubin, and is actually a molecular integrator of key cellular processes that help protect neurons from damage.

Chirag Vasavda, MD, PhD, Study First Author and Physician, Harvard Medical School and Massachusetts General Hospital

“This work highlights the long-term value of mechanistic discovery,” stated Ruchita Kothari, Graduate Student and Study Co-First Author, Johns Hopkins University.

“Our research identifies a vital non-canonical of BVRA that plays key roles in neuronal signaling, which may be harnessed for therapeutic benefits,” added Paul.

Paul plans to investigate how the BVRA and NRF2 connection fails in mouse models of Alzheimer's disease in the future.

Our efforts underscore the power of multidisciplinary collaboration fueled by long-term investment in scientific research to address complex biological challenges.

Bindu Paul, M.S., Ph.D., Study Lead and Associate Professor, Pharmacology, Psychiatry and Neuroscience, Johns Hopkins University School of Medicine