Researchers have created a powerful platform for investigating the roles of genes involved in metabolism, which encompasses all essential chemical reactions for sustaining life. They utilized the innovative GeneMAP (Gene-Metabolite Association Prediction) platform to pinpoint a gene that plays a crucial role in mitochondrial choline transport.
A diverse team of researchers has developed an innovative platform to delve into the functions of metabolism-related genes, which are vital for supporting various life-sustaining chemical reactions.
The researchers leveraged this new platform, named GeneMAP, to uncover a gene essential for transporting choline to mitochondria. The resource and its discoveries were recently featured in the journal Nature Genetics.
“Our goal was to gain a deeper understanding of a fundamental question: ‘How does genetic variation shape our unique biochemical characteristics?'” said Eric Gamazon, PhD, who is an associate professor of Medicine in the Division of Genetic Medicine at Vanderbilt University Medical Center and the senior author of the study alongside Kivanç Birsoy, PhD, from The Rockefeller University.
Metabolic reactions are crucial for processes such as nutrient absorption, energy generation, waste elimination, and the creation of vital cellular components like proteins, lipids, and nucleic acids. Approximately 20% of genes involved in coding for proteins are dedicated to metabolism, including those responsible for small-molecule transporters and enzymes, as stated by Gamazon.
Anomalies in metabolic functions are linked to various conditions, including neurodegenerative disorders and cancer.
“Despite extensive research efforts over the years, many metabolic genes still lack known molecular functions. This challenge stems from the vast structural and functional diversity of these proteins,” Gamazon explained.
To address the need to understand the functions of “orphan” transporters and enzymes, which are proteins with unidentified substrates, the researchers developed the GeneMAP discovery platform. By utilizing data from two large-scale human studies linking the genome and transcriptome with metabolism, they showcased that GeneMAP can uncover known gene-metabolite associations and reveal new connections. Additionally, they demonstrated that the metabolic networks generated by GeneMAP can aid in determining the identity of uncharacterized metabolites.
To validate newly discovered gene-metabolite associations, the researchers concentrated on their most significant finding (SLC25A48-choline) and conducted in vitro biochemical experiments. SLC25A48 is a mitochondrial transporter that was previously not linked to a specific substrate for transport. Choline is a crucial nutrient involved in multiple metabolic processes and in forming cell membrane lipids.
The team revealed that SLC25A48 affects plasma choline levels genetically. Additionally, they carried out assays on radioactive mitochondrial choline uptake and isotope tracing experiments to demonstrate that the absence of SLC25A48 hinders mitochondrial choline transport and the production of the downstream choline metabolite, betaine.
Furthermore, they explored the implications of the link between SLC25A48 and choline on the human medical phenome (comprising symptoms, traits, and diseases recorded in electronic health records) using extensive biobanks (UK Biobank and BioVU), identifying associations with eight diseases.
“What’s particularly exciting about this study is the interdisciplinary nature of it — combining genomics and metabolism to identify a long-sought mitochondrial choline transporter,” noted Gamazon. “Based on the thorough in silico validations in independent datasets and the successful experimental studies, we believe our approach can aid in identifying the substrates of various enzymes and transporters, effectively ‘deorphanizing’ these metabolic proteins.”
Birsoy is the Chapman-Perelman Associate Professor and heads the Laboratory of Metabolic Regulation and Genetics at The Rockefeller University, holding positions as a Searle and Pew-Stewart Scholar. Co-authors of this study include Artem Khan, Gokhan Unlu, PhD, (who received his doctoral degree from Vanderbilt), Yuyang Liu, Ece Kilic, and Timothy Kenny, PhD, from Rockefeller, along with Phillip Lin from VUMC.
This research received support from the National Institutes of Health (grants F99CA284249, F32DK127836, R01DK123323, R01HG011138, R01GM140287, R56AG068026, U24OD035523, R35HG010718), the Boehringer Ingelheim Fonds PhD Fellowship, and the Damon Runyon Cancer Research Foundation.
