Hepatic mitochondrial conversion of acetyl-CoA into ketone bodies during prolonged fasting, ketogenic diet, or insulin deficiency. Acetyl-CoA from accelerated β-oxidation condenses to acetoacetyl-CoA → HMG-CoA (via mitochondrial HMG-CoA synthase 2, the rate-limiting enzyme — distinct from the cytosolic HMGCS1 of cholesterol synthesis) → acetoacetate → β-hydroxybutyrate (the dominant circulating ketone, reduced by BDH1) or → acetone (spontaneous decarboxylation; responsible for the fruity breath of DKA). Extrahepatic tissues reverse the steps to regenerate acetyl-CoA for fuel.
Organ Systems
endocrine
digestive
Pathway Steps
acetyl-coa → acetoacetyl-coa — via thiolase. Thiolase condenses two acetyl-CoA (reverse of the β-oxidation thiolase step) — so ketogenesis draws on the acetyl-CoA flooding mitochondria in fasting/low-carb states when fat oxidation outpaces TCA capacity (oxaloacetate diverted to gluconeogenesis).
acetoacetyl-coa → hmg-coa — via HMG-CoA synthase 2 (mitochondrial; HMGCS2 — RATE-LIMITING). Mitochondrial HMG-CoA synthase 2 (HMGCS2) is the rate-limiting, ketogenesis-committed enzyme — distinct from the cytosolic HMGCS1 of cholesterol synthesis — and is induced by fasting via PPARα/FGF21, restricting ketone production largely to the liver.
hmg-coa → acetoacetate — via HMG-CoA lyase. HMG-CoA lyase cleaves HMG-CoA to acetoacetate plus acetyl-CoA; though HMG-CoA is shared with cholesterol synthesis, this mitochondrial pool is committed to ketones. Lyase deficiency causes hypoketotic hypoglycemia with metabolic crises.
acetoacetate → beta-hydroxybutyrate — via BDH1 — interconvertible; β-HB is the dominant circulating ketone. BDH1 interconverts acetoacetate and β-hydroxybutyrate; β-HB is the dominant circulating ketone and the form home meters measure. The acetoacetate:β-HB ratio reflects mitochondrial NADH/NAD⁺ redox state.
acetoacetate → acetone — via spontaneous decarboxylation (no enzyme). Acetoacetate spontaneously (non-enzymatically) decarboxylates to acetone, which is exhaled — the fruity breath of fasting/ketoacidosis and the basis of breath-ketone meters.