Chapter 22: Fatty Acid Oxidation & Ketogenesis

Unlike biosynthesis which occurs in the cytosol, fatty acid catabolism takes place within the mitochondrial matrix, a compartmentalization that allows for precise metabolic control. The process begins with the activation of fatty acids into acyl-CoA by thiokinase, followed by their transport across the inner mitochondrial membrane via the carnitine shuttle, a step regulated by carnitine palmitoyltransferase-I. Once inside the mitochondria, the fatty acid chain undergoes a series of repeating chemical reactions—dehydrogenation, hydration, and cleavage—that sequentially remove two-carbon units as acetyl-CoA while generating the reducing equivalents FADH2 and NADH for the respiratory chain. The chapter details the high ATP yield from this process, such as the net gain of 106 ATP from the common fatty acid palmitate, and notes specialized adaptations for odd-chain fatty acids, which provide glucogenic precursors, and unsaturated fats. Furthermore, it discusses peroxisomal oxidation for very-long-chain fatty acids and its clinical relevance in disorders like Zellweger syndrome. When fatty acid breakdown exceeds the capacity of the citric acid cycle, particularly in the liver, the excess acetyl-CoA is diverted into ketogenesis. This pathway produces acetoacetate, D-3-hydroxybutyrate, and acetone, which serve as vital alternative fuels for extrahepatic tissues like muscle and brain during periods of glucose scarcity. The regulation of ketogenesis is highlighted at three critical junctures: the mobilization of lipids from adipose tissue, the inhibition of mitochondrial entry by malonyl-CoA, and the partitioning of acetyl-CoA between energy production and ketone synthesis. Clinical conditions such as carnitine deficiency, Jamaican vomiting sickness caused by hypoglycin, and the life-threatening ketoacidosis associated with uncontrolled diabetes or prolonged starvation are examined to illustrate the metabolic consequences of impaired fatty acid oxidation.