Researchers from the Redoxoma Research Center, led by Alicia Kowaltowski and Mauricio Baptista from the Instituto de Química at the Universidade de São Paulo (USP), have discovered a new mechanism by which red light enhances mitochondrial oxygen consumption in keratinocytes, the most abundant cell type in the skin. The study showed that these cells act as metabolic sensors capable of reacting to different colors in sunlight.

According to Baptista, the study represents a conceptual shift in the field. “I’m very excited about this result,” he says. “The work breaks the paradigm that red light directly modulates oxidative phosphorylation. We demonstrated that another process, likely occurring in the cytoplasm, enhances this mitochondrial function. There is a metabolic signal that leads to the oxidation of fatty acids and increases oxygen consumption.” This new interpretation, the researcher states, is more biologically coherent.

“The project began with the idea of ​​investigating how visible light affects mitochondria, which are the center of cellular metabolism,” says doctoral student Manuel Alejandro Herrera, first author of the article, published in FEBS Letters. “We wanted to understand how the cells most exposed to solar radiation, keratinocytes, behave in response to different wavelengths, since sunlight is composed of several color bands. We usually study the effects of ultraviolet radiation and the damage caused by sunlight, but we have a much greater gap in our understanding of other types of light.“

Our skin is constantly exposed to sunlight, and understanding how it responds to this exposure is essential to assess the health impacts of radiation. Traditionally, ultraviolet radiation (UVA and UVB) has been associated with cellular damage, such as phototoxic reactions that oxidize cellular components and can lead to premature aging and skin cancer.

In recent years, researchers have also begun exploring the effects of other bands of the solar spectrum. Red light, for example, is a low-energy radiation capable of penetrating the skin and possibly inducing stimulating effects. Until now, however, the molecular mechanisms responsible for these effects have been poorly understood.

Metabolic Reprogramming

Through metabolic flux analysis, the researchers showed that different wavelengths of light have distinct effects on keratinocytes. While UVA radiation suppresses energy production and blue and green light compromise cell viability, red light has the opposite effect, stimulating oxidative metabolism. They found that this beneficial effect results from the activation of the enzyme AMPK, which activates fatty acid, increasing electron supply to the respiratory chain and cellular respiration.

AMPK acts as an energy sensor, maintaining the balance between ATP and AMP and triggering adaptive metabolic responses. According to Kowaltowski, “This is a completely new way to activate the fatty acid oxidation pathway. Our work has uncovered a signaling pathway that had never been described as modulated by light before, and that is extremely central to cellular metabolism.“

Activation of AMPK inhibits ACC (acetyl-CoA carboxylase), which simultaneously blocks fatty acid synthesis and channels free fatty acids (FFA) toward mitochondrial β-oxidation. The researcher emphasizes that light does not directly affect the mitochondrial machinery but acts as a broader metabolic signal.

To monitor keratinocyte metabolism in real time, the researchers used the Seahorse XF and Resipher systems, which allow continuous, noninvasive measurement of oxygen consumption in cultured cells. The data show that the increase in cellular respiration persisted for up to 48 hours after red light exposure, disappearing only on the third day. This is a pattern typical of metabolic reprogramming, suggesting enzymatic changes rather than direct light activation.

Other skin cell types, such as fibroblasts and melanocytes, did not respond in the same way to red light, indicating a specific signaling pathway.

The metabolic activation observed in cells exposed to red light does not imply a loss of lipids, but rather a change in how they are used. “These cells have an activation of the fatty acid oxidation pathway and a decrease in free fatty acid levels, but there is no reduction in triacylglycerol or cholesterol,” the researcher explains. In other words, we can’t say that the cells are “burning fat.“

Light-Based Treatments

Light-based technologies are increasingly used to treat diverse health conditions. In photobiomodulation, for instance, specific wavelengths of light are applied to the skin to produce therapeutic effects such as pain relief and accelerated wound healing. These effects are valuable in managing inflammatory, neurological, and musculoskeletal disorders.

“It has been stated for decades that red light “activates mitochondria”, but there is little data that provides a broader view of cellular metabolism,” says Baptista. “It activates mitochondria, but how? What is the real effect? ​What are the consequences?” He notes that the strength of this study also lies in its experimental approach. “This effect has never been investigated in skin cells with the rigor of a metabolism laboratory.“

For Kowaltowski, understanding the molecular mechanisms behind light’s effects is essential to improve photobiomodulation therapies. “Many people use light treatments without understanding the molecular basis of what’s happening,” she observes. “Light can act through different mechanisms, including heat, and without distinguishing these processes, it’s impossible to improve treatments or understand why they work.” Identifying the molecules involved, she adds, is what allows the development of more specific and effective approaches.

To further investigate the effects of red light on the skin, Herrera is currently conducting part of his PhD at the Medical University of Vienna, supported by a FAPESP Research Internship Abroad (BEPE) fellowship. “We’re now focused on understanding more deeply how red light affects skin development,” he explains. For that, he is using primary cells isolated from dermatology patients and three-dimensional skin models grown in the laboratory, which more closely reproduce human tissue. “We are reconstructing skin from scratch and irradiating these samples with red light.“

The article “Mitochondrial fatty acid oxidation is stimulated by red light irradiation”, by Manuel Alejandro Herrera, Camille C. Caldeira da Silva, Maiza Von Denz, Mauricio S. Baptista and Alicia J. Kowaltowski, is open access thanks to an agreement between the Coordination for the Improvement of Higher Education Personnel (CAPES) and Wiley, and can be accessed at here.