Discoveries
Metabolism
Metabolism
We are working to understand human metabolism and what happens when it fails—a more important problem than ever given the increasing burden that diabetes and other metabolic dysfunctions have on human health and society.

Discoveries

IN THIS ISSUE

JOURNAL OF CELL BIOLOGY
01/2025

Don’t stress! This protein is directing mitochondrial rescue missions

Because mitochondria are so important for survival, cells have developed a specialized information pipeline, called mitochondrial retrograde signaling pathways, to get periodic updates on their mitochondria’s health. One of these pathways evaluates mitochondrial fitness by sensing how much mitochondrial DNA (mtDNA) is present in the cell—low levels of mtDNA can signal mitochondrial stress and encourage inflammation. Until now, the pathway controlling mtDNA sensing in mammalian cells was poorly understood.

Research from Professor Gerald Shadel, postdoctoral researcher Alva Sainz, and colleagues identified the protein FAM43A as an early responder to mtDNA depletion in mammalian cells. When FAM43A levels are suddenly reduced, a mitochondrial rescue mission ensues, increasing mitochondrial mass and rescuing mtDNA levels. Their findings enrich scientific understanding of mitochondrial stress, which could inform future treatments for many neurological, metabolic, and aging-related disorders.

CELL REPORTS
03/2025

Astrocyte protein linked to healthy brain connections could inspire new treatments for Alzheimer’s

The connection between two neurons, called a synapse, allows information to flow from one brain cell to the next. Healthy synapses enable us to think, learn, and make memories. However, the exact process for creating and stabilizing new synapses are poorly understood.

Professor Nicola Allen, graduate student Alexandra Bosworth, and colleagues have now shown that nonneuronal brain cells called astrocytes are surprisingly critical for maintaining healthy synapses. Using a mouse model, the researchers found that astrocytes produce a protein called glypican 5 that is necessary for the proper maturation and refinement of synapses. Without glypican 5, synapses lose structural maturity and cause the pre- and post-synaptic portions of neighboring neurons to shrink. This information could now influence the development of new therapeutics for brain disorders that involve synaptic dysfunction, including Alzheimer’s disease and frontotemporal dementia.

PNAS
04/2025

Peptide imitation is the sincerest form of plant flattery

Industrial farming practices often deplete the soil of important nutrients and minerals, leaving farmers to rely on artificial fertilizers to support plant growth. In fact, fertilizer use has more than quadrupled since the 1960s, but this comes with serious consequences. Fertilizer production consumes massive amounts of energy, and its use pollutes the water, air, and land.

Assistant Professor Lena Mueller, graduate student Sagar Bashyal, and colleagues are proposing a new solution to help kick this unsustainable fertilizer habit. In their new study, the researchers identified a key molecule produced by plant roots, a small peptide called CLE16, that encourages plants and beneficial soil fungi to interact with each other. They say boosting this symbiotic relationship, in which the fungi provide mineral nutrients to the plants through CLE16 supplementation, could be a more natural and sustainable way to encourage crop growth without the use of harmful artificial fertilizers.

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PNAS
05/2025

Estrogen-related receptors could be key to treating metabolic and muscular disorders

Across the body, tiny bean-shaped structures called mitochondria turn the food we eat into usable energy. This cellular-level metabolism is especially important in muscle cells, which require a lot of fuel to power our movement. However, 1 in 5,000 people are born with dysfunctional mitochondria, and many others develop metabolic dysfunction later in life in association with aging or diseases like cancer, multiple sclerosis (MS), heart disease, and dementia.

Mitochondrial dysfunction is difficult to treat, but recent findings from Professor Ronald Evans, staff scientist Weiwei Fan, and colleagues show that a group of proteins called estrogen-related receptors could be a new and effective therapeutic target. The scientists discovered that estrogen-related receptors play an important role in muscle cell metabolism, especially during exercise. When our muscles need more energy, estrogen-related receptors can increase the number of mitochondria and enhance their energetic output within muscle cells. The findings indicate that developing a drug to boost estrogen-related receptors could be a powerful way to restore energy supplies in people with metabolic disorders, such as muscular dystrophy.

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Nature Structural & Molecular Biology
05/2025

Action! Proteins critical to healthy brain development captured on film

Our cells rely on microscopic highways and specialized protein vehicles to move everything inside them—from positioning organelles to disposing of cellular garbage. These vehicles, called motor proteins, are indispensable to cellular function and survival, and their dysfunction can lead to severe neurodevelopmental and neurodegenerative disorders. For example, dysfunction of the motor protein dynein or its partner protein Lis1 can lead to a rare fatal birth defect called lissencephaly, or “smooth brain.” Therapeutics that target and restore dynein or Lis1 function could change those dismal outcomes, and developing those therapeutics depends on thoroughly understanding how dynein and Lis1 interact.

Assistant Professor Aga Kendrick, Salk colleagues, and UC San Diego collaborators captured high-resolution movies of Lis1 activating dynein. The movies allowed the team to catalogue 16 shapes that the two proteins take as they interact, some of which have never been seen before. These insights will be foundational for designing future therapeutics that can target these structures and restore dynein and Lis1 function.

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Nature
05/2025

Cannabis pangenome reveals potential for medicinal and industrial use

Cannabis has been a globally important crop for millennia. While best known today as marijuana for its psychoactive cannabinoid THC (tetrahydrocannabinol), cannabis has historically been a cornerstone of human civilization, providing seed oil, textiles, and food for more than 10,000 years. Today, cannabis remains an understudied and underutilized resource, but United States legislation passed in 2014 and 2018 has re-energized cannabis crop development for medicinal, grain, and fiber applications.

Research Professor Todd Michael and postdoctoral researchers Ryan Lynch and Lillian Padgitt-Cobb, alongside Salk colleagues and collaborators from Oregon CBD, Oregon State University, and the HudsonAlpha Institute of Biotechnology, have created the most comprehensive, high-quality, and detailed genetic atlas of cannabis to date. The team analyzed 193 different cannabis genomes (entire sets of genetic information), revealing an unprecedented diversity, complexity, and untapped opportunity within this foundational agricultural species. Their findings set the stage for transformative advances in cannabis-based agriculture, medicine, and industry.

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