Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia

Abstract

Keloids exhibit metabolic reprogramming including enhanced glycolysis and attenuated oxidative phosphorylation. Hypoxia induces a series of protective responses in mammalian cells. However, the metabolic phenotype of keloid fibroblasts under hypoxic conditions remains to be elucidated. The present study aimed to investigate glycolytic activity, mitochondrial function and morphology, and the HIF1α and PI3K/AKT signaling pathways in keloid fibroblasts (KFB) under hypoxic conditions. Our results showed that hypoxia promoted proliferation, migration invasion and collagen synthesis and inhibited apoptosis in KFB. The mRNA levels, protein expressions and enzyme activities of glycolytic enzymes in KFB were higher than those in normal skin fibroblasts (NFB) under normoxia. Moreover, hypoxia remarkedly upregulated glycolysis in KFB. Decreased activities of mitochondrial complexes and abnormal mitochondria were detected in KFB under normoxic conditions and the damage was aggravated by hypoxia. An intracellular metabolic profile assay suggested hypoxia increased glycolytic parameters except glycolytic reserve but inhibited the key parameters of mitochondrial function apart from H + leak. Protein levels of HIF1α and phosphorylation levels of the PI3K/AKT signaling pathway were upregulated in the context of 3% oxygen. Enhanced total reactive oxygen species (ROS), mitochondrial ROS (mitoROS) and antioxidant activities of KFB were observed in response to hypoxia. Additionally, autophagy was induced by hypoxia. Our data collectively demonstrated potentiated glycolysis and attenuated mitochondrial function under hypoxia, indicating that altered glucose metabolism regulated by hypoxia could be a therapeutic target for keloids.

Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach

“… 46 , 47 This is because hypoxia can significantly affect mitochondrial activity, impairing muscle energy generation through oxidative phosphorylation, where oxygen is required as an electron‐terminal receptor, resulting in a decrease in adenosine triphosphate (ATP), which is required for protein synthesis and muscle contraction. 48 , 49 , 50 …”

GLUT-1 Enhances Glycolysis, Oxidative Stress, and Fibroblast Proliferation in Keloid

“…For glycolysis in keloids, Wang et al showed that in hypoxia-promoted proliferation, GLUT-1 expression was enhanced, as well as migration and collagen synthesis, and autophagy in KF [66]. However, in that study, no blocking measures for GLUT-1 or other glycolytic enzymes were performed.…”

Epigenetic Influences on Wound Healing and Hypertrophic-Keloid Scarring: A Review for Basic Scientists and Clinicians

“…ROS is associated with increased expression of the GLUT1 glucose transporter in the skin of patients affected by diabetes [ 26 ], psoriasis [ 27 ], and keloids [ 16 ], thereby providing a biochemical marker for oxidative stress and the potential for developing fibroproliferative lesions. Increased ROS in fibroblasts from keloid scar tissue exposed to hypoxia [ 28 ] also suggests that oxidative stress likely plays an important role in the development and maintenance of keloids. Figure 3 demonstrates the connection between ROS and alterations in DNA and fibroblasts for hypertrophic-keloid scarring and carcinogenesis.…”