Metabolic Disease

Most cellular energy is derived from the mitochondrial electron transport chain, which reduces oxygen to water in a series of steps to drive the formation of the high-energy compound ATP. The Krebs cycle creates high-energy intermediates that it feeds to the electron transport chain, the energy of which ultimately is derived from a two-carbon compound called acetate, which is broken down successively to carbon dioxide. Acetate is derived from several pathways of amino acid, carbohydrate, and fat metabolism.

Thus, many pathways of metabolism feed into the Krebs cycle to drive oxidative metabolism in a web of processes requiring hundreds of enzymes. When there are defects in the Krebs cycle or the electron transport chain, one result may be ketoacidosis, which is due to the accumulation of lactic acid and ketone bodies.

The lack of cellular energy may be manifest in many cellular processes and can affect several tissues and organ systems, particularly those that are most dependent upon oxidative metabolism for energy. The brain and muscles are generally affected first, which can cause developmental delay, neurological crises—including episodes of coma, stroke-like events, and seizures—and muscle weakness or cardiomyopathy. Kidney function—most often the tubular function required for retention of electrolytes—may also be affected. Endocrine (hormone) systems may also be affected, resulting in conditions such as diabetes mellitus (caused by effects on the pancreas or by sensitivity to insulin in muscle and fat cells) or adrenal insufficiency (from effects on the adrenal glands).

Disorders of mitochondrial oxidative metabolism are very variable in terms of age of onset, severity, specific symptoms, and clinical course. Even the inheritance patterns of mitochondrial diseases are heterogeneous. Most are inherited in the usual autosomal recessive manner (although the chromosomal locations of only a few of the relevant genes are known). A few are inherited from defects in the mitochondrial DNA, which is passed on in the maternal line.

The mitochondrion contains a circular chromosome of about 16,500 bases. It codes for thirteen components of the electron-transport chain, as well as transfer RNA molecules and ribosomal RNAs required for their expression. Since there are multiple copies of mitochondrial DNA and there may be mixtures of normal and abnormal mitochondrial DNA (a phenomenon known as heteroplasmy), the precise proportion of mutated mitochondrial DNA may vary in an unpredictable manner from individual to individual within a family, and from tissue to tissue within an individual. There may also be variations within an individual tissue over time, adding to the unpredictability of mitochondrial disease and the difficulty in the diagnosis.