ATP — Cellular Energy Currency

The vast majority is made in mitochondria by oxidative phosphorylation. Pyruvate from glycolysis enters mitochondria, is oxidized to acetyl-CoA, and feeds the citric acid cycle. NADH and FADH2 generated by the cycle deliver electrons to the electron transport chain (complexes I-IV), pumping protons across the inner mitochondrial membrane. The proton-motive force drives ATP synthase (complex V), spinning a rotary motor that synthesizes ATP from ADP and inorganic phosphate. Glycolysis itself yields only 2 ATP per glucose without oxygen.

Each NADH yields ~2.5 ATP and each FADH2 ~1.5 ATP through the electron transport chain. Aerobic glucose oxidation theoretically yields ~38 ATP, but accounting for transport costs the practical yield is ~30-32 ATP per glucose — about 40% thermodynamic efficiency, far higher than internal combustion engines. The remaining energy is lost as heat, which is a feature, not a bug — brown adipose tissue uses uncoupling protein 1 to short-circuit ATP synthesis specifically to generate heat (non-shivering thermogenesis).

Almost everything. Sodium-potassium ATPase consumes about a quarter of basal energy maintaining ion gradients. Calcium pumps maintain low cytosolic calcium. Myosin uses ATP for cross-bridge cycling in muscle. Protein synthesis costs ~4 ATP per peptide bond. Active transport across membranes (proton pumps, ABC transporters) is ATP-driven. Phosphorylation cascades in signaling consume ATP (kinases hydrolyze ATP to phosphorylate substrates). The brain alone uses ~20% of body ATP at rest.

AMP-activated protein kinase (AMPK) senses the AMP:ATP ratio. When ATP falls and AMP rises, AMPK activates catabolic pathways (fatty acid oxidation, glucose uptake) and inhibits anabolic ones (cholesterol, protein synthesis). Metformin activates AMPK indirectly and is a first-line diabetes drug. The mechanistic target of rapamycin (mTOR) responds inversely — high energy and amino acids activate mTOR, driving growth and inhibiting autophagy. Together, AMPK and mTOR coordinate metabolic adaptation.

Skeletal muscle stores energy as phosphocreatine, a high-energy phosphate buffer. Creatine kinase rapidly transfers phosphate to ADP, regenerating ATP during bursts of activity. This buffer covers the first ~10 seconds of maximal exertion. Glycolysis (anaerobic) sustains the next minute. Beyond that, oxidative phosphorylation must take over. Creatine supplementation increases muscle phosphocreatine stores, supporting modest gains in high-intensity training. Creatine kinase release is also the basis of CK testing for muscle injury.

Mitochondrial DNA encodes 13 protein subunits of the electron transport chain plus rRNAs and tRNAs. Mutations cause heteroplasmic disease — different proportions of mutant mtDNA across tissues produce varied severity. Energy-demanding tissues (brain, heart, skeletal muscle, eye) suffer most. Examples include MELAS, MERRF, Leber's hereditary optic neuropathy, and Leigh syndrome. Mitochondrial myopathies cause exercise intolerance, lactic acidosis, and ragged red fibers on muscle biopsy. Mitochondrial replacement therapy is now licensed for prevention in some jurisdictions.

When oxygen delivery cannot keep pace with ATP demand, pyruvate from glycolysis is reduced to lactate by lactate dehydrogenase, regenerating NAD+ to keep glycolysis running. The reaction itself is not the source of the acidosis — ATP hydrolysis releases H+, and without aerobic regeneration, those protons accumulate. Causes include shock, sepsis, severe exercise, metformin (in renal failure), cyanide, and mitochondrial dysfunction. Lactate clearance over the first hours of resuscitation is a key prognostic marker in sepsis.