Brown fat is a specialized tissue that has developed a host of important functions over the course of evolution. One of the most critical: the ability to produce heat in response to low temperatures by burning energy. Many animals can maintain their body temperature even in cold environments through the unique capabilities of brown fat.
Adult humans have a similar type of fat, known as beige fat. And while we might rely on this form of fat for survival in frigid climates, there is increasing recognition that this tissue may play important roles in counteracting the metabolic dysregulation in obesity and diabetes.
Dana Farber’s Pere Puigserver, PhD, studies the molecular and cellular mechanisms that underlie the unusual biology of brown fat to not only understand this remarkable tissue, but also the inner workings of other highly metabolically active cells — including tumor cells.
Dana Farber’s Pere Puigserver, PhD
In a recent paper published in the journal Cell, he and his colleagues revealed the architecture of two key respiratory protein complexes that, through a crucial conformational change, enables brown fat to generate more heat in cold conditions.
“What we found is that during adaptations to cold temperatures and the energy demands to generate heat, these proteins in brown fat adopt a new conformation architecture that allows electrons to move faster,” said Puigserver. “When electrons move faster, that means the cells use more oxygen and in turn, produce more heat.”
The proteins in question — a conglomerate of two multi-protein machines, known as respiratory complex I (CI) and complex III (CIII) — reside on the inner membrane of the mitochondria. They function as part of a chain of different protein complexes that transfer electrons from one complex to another. This flow of electrons is like a battery of sorts and is the driving force for generating heat.
Puigserver and his colleagues studied these protein complexes in their endogenous form in the brown fat cells of mice housed at different temperatures. Using cryo-electron microscopy to visualize the intricate protein structures at high resolution, they were able to discern the conformational change of the CI-CIII super-complex at cold temperatures.
In addition to discovering this architectural shift, the scientists also explored how it happens. And it turns out that the flexibility of the inner mitochondrial membrane is a key factor.
Different types of lipids influence how foldable the membrane is. In cold temperatures, a change in lipid content allows the inner mitochondrial membrane to fold more easily, which drives the conformational change and shortens the distance between CI and CIII. With this shorter path, electrons can flow more quickly and that helps ramp up heat generation.
Now, Puigserver and his colleagues are working to extend their findings in several ways. First, they seek to better understand the mechanics of the shift in lipid composition. They will also study other cell types, such as skeletal muscle and cardiac muscle during exhaustive exercise, to see if the changes they identified in brown fat also occur in those cells.
In addition, they will examine tumor cells to see if a similar CI-CIII conformational change exists. Drugs that target the protein complexes within the inner mitochondrial membrane have been tested in clinical cancer trials, but they failed due to toxicity. A deeper understanding of the biology could help spark a new, more successful approach.
“It’s critical to understand the biology of brown fat,” said Puigserver. “We can learn not only how brown fat itself works, but also understand more deeply how very metabolically active cells — like tumors cells, skeletal muscle cells, and others — function in both health and disease.”
Written by: Dana-Farber Editorial Team