Researchers Identify a Novel PARP-Like Enzyme in Mitochondria
Researchers identify an enzyme called NEURL4 that is active in the mitochondria and similar to PARP1, an enzyme studied for its role in repairing damaged DNA and regulating gene expression.
They confirmed that NEURL4 activity is required for the maintenance of mitochondrial DNA (mtDNA) integrity.
This study is an important step in understanding how cells maintain homeostasis and respond to oxidative stress — and hopefully for future research on the treatment of diseases with a mitochondrial component, like aging.
Plus, NEURL4 may also be relevant for the treatment of male infertility. This research indicates that reduced NEURL4 expression in mice is associated with increased mtDNA deletions and markers of male infertility, such as reduced sperm count and increased sperm clumping.
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For the first time, researchers from Boston University School of Medicine (BUSM) have identified an ADP-ribosyltransferase enzyme that is active in the mitochondria (the organelle that generate most of the chemical energy needed to power biochemical reactions in cells) and characterized its activity. ADP-ribosyltransferases are enzymes that play a role in the modification of other proteins. The activity of this new mitochondrial enzyme, called NEURL4, is similar to that of PARP1, a nuclear enzyme well studied for its critical role in DNA damage repair and regulation of gene expression.
To characterize the enzymatic activity of NEURL4, the team led by first and co-corresponding author Maria Dafne Cardamone, PhD, former research assistant professor of biochemistry at BUSM, first performed in-vitro enzymatic assays. Then they generated a cell line in which NEURL4 was deleted using a gene editing system. From there they used mass spectrometry to compare the modifications on mitochondrial proteins in wild-type ("normal") versus cells without NEURL4.
According to the researchers this approach led them to identify a number of mitochondrial proteins as targets of NEURL4, including mitochondrial LIG3, a protein involved in the repair of damaged mitochondrial DNA and confirmed that NEURL4 activity is required for the maintenance of mitochondrial DNA (mtDNA) integrity.
While this study does not have any direct implication for clinical treatments, the team says it represents an important step in understanding how cells maintain homeostasis and respond to oxidative stress. "While this will not directly improve people's quality of life, we hope it will provide fertile grounds for new translational applications for the treatment of diseases with a mitochondrial component" said co-corresponding author Valentina Perissi, PhD, associate professor of biochemistry and co-director of the Boston Nutrition Obesity Research Center at BUSM.
The researchers believe future studies investigating how NEURL4-mediated modifications of specific mitochondrial proteins affect mitochondrial functions could lead to the identification of novel regulatory strategies to target for therapeutic purposes. A better understanding of NEURL4 biology may also prove relevant for the treatment of male infertility. Mitochondrial DNA deletions are linked with reduced sperm mobility and infertility in both mice and humans and this research indicates that reduced NEURL4 expression in mice is associated with increased mtDNA deletions and markers of male infertility, such as reduced sperm count and increased sperm clumping.
- Maria Dafne Cardamone, Yuan Gao, Julian Kwan, Vanessa Hayashi, Megan Sheeran, Junxiang Xu, Justin English, Joseph Orofino, Andrew Emili, Valentina Perissi. Neuralized-like protein 4 (NEURL4) mediates ADP-ribosylation of mitochondrial proteins. Journal of Cell Biology, 2022; 221 (3) DOI: 10.1083/jcb.202101021