It is essential to understand the central role of the TCA cycle in all of aerobic energy metabolism. Thus far, glucose has been regarded as the main substrate for cellular respiration. But while most summary reactions written for chemotrophic energy metabolism assume glucose as the starting compound, we must also note the roles of alternative fuel molecules in cellular energy metabolism and the TCA cycle, especially fats and proteins. Far from being a minor pathway for the catabolism of a single sugar, the TCA cycle represents the main conduit of aerobic energy metabolism in a broad spectrum of organisms from microbes to higher plants and animals.

The role of fats in energy storage has been noted and it is observed that they are highly reduced compounds that liberate more energy per gram upon oxidation than do carbohydrates. For this reason, fats are an important long-term energy storage form for many organisms. Fat reserves are especially important in hibernating animals and migrating birds and also represent a common form in which energy and carbon are stored by plants in their seeds. 

Most fat is stored as deposits of triacylglycerols (also called triglycerides), which are neutral triesters of glycerol and long-chain fatty acids. Catabolism of triacylglycerols begins with their hydrolysis to glycerol and free fatty acids. The glycerol is channeled into the glycolytic pathway by oxidative conversion to dihydroxy-acetone phosphate. The fatty acids are linked to coenzyme A to form fatty acyl CoAs, which are then oxidatively degraded by a sequential, stepwise process that involves the successive oxidation and removal of two-carbon units, generating acetyl CoA and the reduced coenzymes NADH and FADH2.

This sequential process of fatty acid catabolism to acetyl CoA is called ? oxidation because the initial oxidative event in each successive cycle occurs on the carbon atom in the ? position of the fatty acid. Thus, the fatty acids derived from fats, like the pyruvate derived from carbohydrates, are oxidatively converted into acetyl CoA, which is then further catabolised by the TCA cycle. Moreover, the enzymes of fatty acid oxidation are localised to the mitochondrion in many (though not all) eukaryotic cells, so the acetyl CoA derived from fats is usually generated and catabolised within the same cellular compartment.

Proteins are not regarded primarily as energy sources because they have more fundamental roles in the cell — as enzymes, transport proteins, hormones and receptors, for example. But proteins can also catabolised to generate ATP if necessary, especially when carbohydrates and lipid stores are depleted or not available. In animals, protein catabolism is prominent under conditions of fasting or starvation, or when the dietary intake of proteins exceeds the need for amino acids. In plants, catabolism of proteins to free amino acids provides building blocks for protein synthesis during the germination of protein-storing seeds. In addition, all cells eventually undergo a turnover of proteins and protein-containing structures, and the amino acids to which the proteins are degraded can either be recycled into proteins or degraded oxidatively to yield energy.

Protein catabolism begins with hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain. The process is called proteolysis, and the enzymes responsible for this are called proteases. The products of proteolytic digestion are small peptides and free amino acids. Further digestion of peptides is catalysed by peptidases, which either hydrolyse internal peptide bonds (endopeptidases) or remove successive amino acids from the end of the peptide (exopeptidases).

Free amino acids, whether ingested as such or obtained by the digestion of proteins, can be catabolised for energy. Generally, these alternative substrates are converted to intermediates of mainstream catabolism in as few steps as possible. In spite of their number and chemical diversity, all these pathways eventually lead to a few key intermediates in the TCA cycle, notably acetyl CoA, a-ketoglutarate, oxaloacetate, fumarate and succinyl CoA.

Of the 20 amino acids found in proteins, three give rise to TCA cycle intermediates or precursors directly. These are the amino acids alanine, aspartate and glutamate, which can be converted to pyruvate, oxaloacetate and a-ketoglutarate, respectively. All the other amino acids require more complicated pathways, often with many intermediates.