Metabolism

Whitehead Member David Sabatini has identified the methionine sensor in the mTOR pathway, which is a crucial metabolic pathway in cells. His work provides interesting data suggesting that the anti-aging and anti-diabetes effects of low methionine and mTOR inhibition may be connected.

A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth.  The researchers’ findings also implicate a new protein, SLC38A9, as a potential drug target in pancreatic cancer. 

For the first time, Whitehead Institute scientists have documented a direct link between deletions in two genes—fam57ba and doc2a—in zebrafish and certain brain and body traits, such as seizures, hyperactivity, large head size, and increased fat content. Both genes reside in the 16p11.2 region of the genome, which has been linked to multiple brain and body disorders in humans, including autism spectrum disorder, developmental delays, seizures, and obesity.

Cultured human cells are the foundation for disease and drug research. Now Whitehead Institute researchers have designed a growth medium that more closely resembles the cells’ environment in the body—and demonstrated that, relative to decades-old recipes that have remained the workhorses of cell culture studies, it significantly alters the cells’ inner workings.

Prize bestowed for discovery of the mTOR pathway’s impact on age-related diseases

Parkinson’s disease (PD) and other “synucleinopathies” are known to be linked to the misfolding of alpha-synuclein protein in neurons. Less clear is how this misfolding relates to the growing number of genes implicated in PD through analysis of human genetics. Two new studies from researchers affiliated with Whitehead Institute and Massachusetts Institute of Technology explain how they used a suite of novel biological and computational methods to shed light on the question.

Whitehead Institute researchers have elucidated how the growth-regulating metabolic pathway known as mTORC1 (for mechanistic target of rapamycin complex 1) senses the amino acid arginine. This nutrient sensor may represent a novel therapeutic target for controlling mTORC1, whose activity is often dysregulated in a variety of diseases, including diabetes and cancer. 

Whitehead Institute scientists have at last answered the long-standing question of how the growth-regulating pathway known as mechanistic target of rapamycin complex 1 (mTORC1) detects the presence of the amino acid leucine—itself a key player in modulating muscle growth, appetite, and insulin secretion.

Countering the prevailing theory that cellular hydrogen peroxide signaling is broad and non-specific, Whitehead Institute scientists have discovered that this reactive oxygen species (ROS) in fact triggers a distinct signal transduction cascade under control of the mitochondrial respiratory chain—the Syk pathway—that regulates transcription, translation, metabolism, and the cell cycle in diverse cell types. Hydrogen peroxide and other ROS mediate cellular responses in aging and myriad common chronic diseases, including diabetes, heart disease, stroke, cancer, and neurodegeneration. Understanding how these signals function may point to new therapy targets for these conditions.

According to Whitehead Institute researchers, cells with malfunctioning mitochondria are unable to proliferate due to a shortage of the amino acid aspartate, not because of an energy crisis, as was once thought. Mitochondrial dysfunction plays a role in a host of relatively rare disorders as well as neurodegenerative disorders, including Parkinson’s disease.