We all learned in high school biology that mitochondria are the powerhouse of the cell. But powering up those cellular engines requires a molecular spark. Now, scientists at the Salk Institute have pinpointed a set of transcription factors—estrogen-related receptors (ERRs)—as essential regulators of mitochondrial metabolism in skeletal muscle, with far-reaching implications for treating degenerative disease, muscle fatigue, and aging. The findings suggest that ERRs may be promising targets for metabolic and muscular disorder therapies, as shown in mice.
The study, titled “Estrogen-Related Receptors Regulate Innate and Adaptive Muscle Mitochondrial Energetics Through Cooperative and Distinct Actions,” shows that two isoforms—ERRα and ERRγ—play distinct yet overlapping roles in maintaining mitochondrial content and function in different muscle types. “We didn’t know what [ERRs] did,” senior author Ronald Evans, PhD, professor and March of Dimes Chair in Molecular and Developmental Biology at Salk, told GEN. “But in the end, [they] became the master regulator of energy in the body—and this was totally unexpected.”
ERRs belong to the nuclear receptor superfamily—DNA-binding proteins that regulate gene expression in response to hormonal and metabolic cues. Evans’ lab discovered ERRs in 1988. He recalls that identifying ERRs was like striking molecular gold. “It goes all the way back to the origin of the animal kingdom… it’s really at the very, very beginning of this explosion that became animals and humans and everything else.”
Despite their name, estrogen-related receptors are not activated by estrogen. Instead, they’re involved in regulating oxidative metabolism, particularly in energy-demanding tissues such as muscle, heart, and brain. Although estrogen-related receptors were discovered more recently than other nuclear receptors, they are believed to be among the earliest to evolve in the animal kingdom. This deep evolutionary origin underscores their fundamental role in energy regulation and supports the idea that ERRs have been central to metabolic adaptation throughout animal physiology, first author Weiwei Fan, PhD, told GEN. “One of our collaborators on the ERR projects, Vincent Giguère, PhD, introduced a new name for ERRs as energy-related receptors. I really like that term because it more accurately describes what they do.”
To understand how ERRs influence muscle energy metabolism, the researchers generated mice lacking ERRα, ERRγ, and ERRβ in muscle tissue. Interestingly, deleting both ERRα and ERRγ didn’t completely wipe out mitochondria—a result that surprised even the researchers. “Well, when you think about it, why would you have three?” said Evans. “The system didn’t want not to have a backup, probably from an evolutionary point of view.”
“Like twins and triplets,” he added, “they’re rare, but that’s one of the special things here. It does just one kind of thing and it does it really well. It’s really solid, but it can be damaged and then you have to kind of replace it.”
“This redundancy is one of the indicators of how important this pathway is for animal and human physiology,” Fan added. He also noted that while mitochondria came first in evolutionary history, nuclear receptors like ERRs evolved later as a way for organisms to adapt energy use to their environment. “They’re central to this adaptivity,” he explained. “The nuclear receptor family evolved only in the animal kingdom… to help organisms move and survive in different environments.”
The Salk team used classical genetic models along with high-throughput sequencing to map ERR binding sites on mitochondrial genes. For future work, they plan to apply newer tools such as single-cell and single-nucleus RNA-seq and CUT&RUN to dissect ERR function at a cellular level across different fiber types. “The exact functions of ERRs in different types of muscle cells are still not completely understood,” said Fan.
At the same time, the team is advancing toward therapeutic development. “Our direct next step is therapeutic development,” said Fan. They are developing mouse models of mitochondrial myopathy to determine whether activating ERRs can reverse or slow disease progression. “We are still developing more mouse models to mimic these mitochondrial myopathies. In the future, we’re going to combine both fields to understand how activating ERRs can be beneficial for these diseases,” said Fan. The team is developing mouse models of mitochondrial myopathy to determine whether activating ERRs can reverse or slow disease progression. “We are still developing more mouse models… to mimic these mitochondrial myopathies. In the future, we’re going to combine both fields to understand activating ERRs, whether it’s beneficial and how it works for these mitochondrial myopathies.”
This also has significant implications for exercise mimetics. Mitochondrial biogenesis is one of the hallmarks of endurance training, but not all patients can tolerate or perform exercise. By activating ERRs pharmacologically, researchers hope to mimic some of the metabolic benefits of exercise. “Certainly, we expected that activating them would give you exercise-mimicking effects,” said Fan. “If you can activate ERRs either genetically or using pharmacological compounds, you would expect it to have some exercise-mimicking effect—at least on the mitochondrial metabolism side.”
Fan and Evans emphasized that ERRs are also more targetable than other key regulators like PGC1α, which lacks DNA-binding ability and relies on partners like ERRs to execute its effects. “That makes these receptors druggable,” said Fan. “We have actually developed some estrogen-related receptor agonists or activators. They have great therapeutic potential.”
As research continues, the idea of enhancing mitochondria through precision activation of nuclear receptors is gaining traction. “This is a very central pathway. It’s been difficult to work with, but actually we’re making good progress,” Evans said. With ongoing advances in genomics and gene delivery tools, researchers hope that ERR-based therapies could one day offer targeted relief for patients facing energy-depleting conditions.
The post Estrogen-Related Receptors Boost Muscle Mitochondria in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.
Ancient origins, modern impact
The study, titled “Estrogen-Related Receptors Regulate Innate and Adaptive Muscle Mitochondrial Energetics Through Cooperative and Distinct Actions,” shows that two isoforms—ERRα and ERRγ—play distinct yet overlapping roles in maintaining mitochondrial content and function in different muscle types. “We didn’t know what [ERRs] did,” senior author Ronald Evans, PhD, professor and March of Dimes Chair in Molecular and Developmental Biology at Salk, told GEN. “But in the end, [they] became the master regulator of energy in the body—and this was totally unexpected.”
ERRs belong to the nuclear receptor superfamily—DNA-binding proteins that regulate gene expression in response to hormonal and metabolic cues. Evans’ lab discovered ERRs in 1988. He recalls that identifying ERRs was like striking molecular gold. “It goes all the way back to the origin of the animal kingdom… it’s really at the very, very beginning of this explosion that became animals and humans and everything else.”
ERRs: Not just for estrogen
Despite their name, estrogen-related receptors are not activated by estrogen. Instead, they’re involved in regulating oxidative metabolism, particularly in energy-demanding tissues such as muscle, heart, and brain. Although estrogen-related receptors were discovered more recently than other nuclear receptors, they are believed to be among the earliest to evolve in the animal kingdom. This deep evolutionary origin underscores their fundamental role in energy regulation and supports the idea that ERRs have been central to metabolic adaptation throughout animal physiology, first author Weiwei Fan, PhD, told GEN. “One of our collaborators on the ERR projects, Vincent Giguère, PhD, introduced a new name for ERRs as energy-related receptors. I really like that term because it more accurately describes what they do.”
To understand how ERRs influence muscle energy metabolism, the researchers generated mice lacking ERRα, ERRγ, and ERRβ in muscle tissue. Interestingly, deleting both ERRα and ERRγ didn’t completely wipe out mitochondria—a result that surprised even the researchers. “Well, when you think about it, why would you have three?” said Evans. “The system didn’t want not to have a backup, probably from an evolutionary point of view.”
“Like twins and triplets,” he added, “they’re rare, but that’s one of the special things here. It does just one kind of thing and it does it really well. It’s really solid, but it can be damaged and then you have to kind of replace it.”
“This redundancy is one of the indicators of how important this pathway is for animal and human physiology,” Fan added. He also noted that while mitochondria came first in evolutionary history, nuclear receptors like ERRs evolved later as a way for organisms to adapt energy use to their environment. “They’re central to this adaptivity,” he explained. “The nuclear receptor family evolved only in the animal kingdom… to help organisms move and survive in different environments.”
Biotech tools and therapeutic horizons
The Salk team used classical genetic models along with high-throughput sequencing to map ERR binding sites on mitochondrial genes. For future work, they plan to apply newer tools such as single-cell and single-nucleus RNA-seq and CUT&RUN to dissect ERR function at a cellular level across different fiber types. “The exact functions of ERRs in different types of muscle cells are still not completely understood,” said Fan.
At the same time, the team is advancing toward therapeutic development. “Our direct next step is therapeutic development,” said Fan. They are developing mouse models of mitochondrial myopathy to determine whether activating ERRs can reverse or slow disease progression. “We are still developing more mouse models to mimic these mitochondrial myopathies. In the future, we’re going to combine both fields to understand how activating ERRs can be beneficial for these diseases,” said Fan. The team is developing mouse models of mitochondrial myopathy to determine whether activating ERRs can reverse or slow disease progression. “We are still developing more mouse models… to mimic these mitochondrial myopathies. In the future, we’re going to combine both fields to understand activating ERRs, whether it’s beneficial and how it works for these mitochondrial myopathies.”
This also has significant implications for exercise mimetics. Mitochondrial biogenesis is one of the hallmarks of endurance training, but not all patients can tolerate or perform exercise. By activating ERRs pharmacologically, researchers hope to mimic some of the metabolic benefits of exercise. “Certainly, we expected that activating them would give you exercise-mimicking effects,” said Fan. “If you can activate ERRs either genetically or using pharmacological compounds, you would expect it to have some exercise-mimicking effect—at least on the mitochondrial metabolism side.”
Fan and Evans emphasized that ERRs are also more targetable than other key regulators like PGC1α, which lacks DNA-binding ability and relies on partners like ERRs to execute its effects. “That makes these receptors druggable,” said Fan. “We have actually developed some estrogen-related receptor agonists or activators. They have great therapeutic potential.”
From bench to bedside
As research continues, the idea of enhancing mitochondria through precision activation of nuclear receptors is gaining traction. “This is a very central pathway. It’s been difficult to work with, but actually we’re making good progress,” Evans said. With ongoing advances in genomics and gene delivery tools, researchers hope that ERR-based therapies could one day offer targeted relief for patients facing energy-depleting conditions.
The post Estrogen-Related Receptors Boost Muscle Mitochondria in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.