1. Mitochondrial β-Oxidation of Long-Chain Fatty Acids
In epidermal keratinocytes and other skin-resident cells, long-chain fatty acids undergo activation to acyl-CoA derivatives in the cytosol, followed by mitochondrial import via the carnitine shuttle system. Within the mitochondrial matrix, successive cycles of β-oxidation cleave two-carbon units from the acyl chain, producing multiple molecules of Acetyl-CoA along with reducing equivalents (NADH and FADH₂).
2. Oxidative Decarboxylation of Pyruvate via Pyruvate Dehydrogenase Complex
Glucose catabolism via glycolysis yields pyruvate in the cytosol, which is subsequently transported into the mitochondrial matrix. There, the multienzyme pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to generate Acetyl-CoA, linking glycolytic flux to the tricarboxylic acid (TCA) cycle and lipid biosynthesis.
3. Catabolic Degradation of Ketogenic Amino Acids
Certain amino acids—particularly the strictly ketogenic ones such as leucine and lysine, as well as the partially ketogenic isoleucine—undergo transamination and subsequent degradation to yield Acetyl-CoA. These pathways are upregulated under catabolic conditions such as prolonged fasting or metabolic stress, contributing to the acetyl-CoA pool in skin cells.
4. Hydrolysis of Intracellular Triglycerides and Subsequent Fatty Acid Oxidation
In sebocytes and lipid-rich compartments of the skin, intracellular triglycerides are hydrolyzed into free fatty acids and glycerol. The liberated fatty acids are subsequently activated and directed into mitochondrial β-oxidation, ultimately yielding Acetyl-CoA to support local energy production and lipid biosynthesis.
Functional Roles of Acetyl-CoA in Cutaneous Physiology
– Lipogenesis: Serves as the primary substrate for de novo fatty acid synthesis, essential for the formation of the epidermal lipid barrier.
– Bioenergetics: Feeds into the TCA cycle, facilitating ATP production under aerobic conditions.
– Steroidogenesis and Cholesterologenesis: Precursor for the synthesis of cholesterol and steroid hormones in skin cells.
– Epigenetic Regulation: Donates acetyl groups for histone acetylation, influencing gene expression programs involved in keratinocyte differentiation and epidermal homeostasis.
