Why SDH is Important
SDH Involvement in Mitochondrial Disease
Mitochondria are the only organelles in the human body to have a separate genome. The mitochondrial DNA (mtDNA) is smaller than nuclear DNA and only codes for subunits of a few enzymes. SDH is entirely coded by nuclear DNA. When a mutation occurs, it can be manifested differently than other complexes in the citric acid cycle or electron transport chain.
Click on this figure for more mitochondrial disease information presented by the UMDF.
Figure 2. Mitochondrion (MIT, Electron microscope photo of a mitochondrion).
Inherited Deficiencies of SDH
A small subset of the human population suffer from mitochondrial disorders, which include enzyme deficiencies. Two such inheritable defects that might involve SDH are Complex II deficiency and Leigh Syndrome. Typically, a child manifests symptoms around the first year. Unfortunately, most children do not live past the age of 2 or 3 (Wallace 2000).
Somatic Mutation Deficiencies
As the human body ages, mistakes become more common in DNA synthesis. Somatic point mutations in the nuclear gene coding for SDH may cause amino acid substitutions that renders it non-functional. Somatic mutations are not typically disseminated through out the body, but restricted to a single organ system in which the mutation originated. Mutations for SDH are commonly found in muscle cells. A deficiency in SDH can cause incorrect functioning in the high-energy muscle system and muscle degradation may result (Schoffner 2000).
Non-SDH Mitochondrial Disorders
There are multiple enzymes in the electron transport chain and in the citric acid cycle. A mutation in any of these enzymes could have serious effects, including reduced enzyme activities or deficiencies. In some cases, other enzymes in the pathway, such as SDH, compensate for the loss of activity. Overexpression of SDH can be one characteristic of the deficiency. By analyzing tissues for overexpression of SDH, doctors can diagnose and treat patients with mitochondrial diseases (Shoffner 2000).
SDH Involvement in Mitochondrial Diseases
Muscle biopsy
Ragged-red fibers, detected by Gomori-Trichrome stain, are associated with some mitochondrial disorders and are characterized by a proliferation of subsarcolemmal and intermyofibrillar mitochondria and a degeneration of myofibrils. A minor increase of glycogen and neutral lipid is also observed. This characteristic, not generally found in SDH deficient cells, is associated with over-expression of SDH. Tests geared to detect overexpression of this complex can detect deficiencies (mtDNA mutations) in other mitochondrial enzymes (Shoffner 2000).
Mitochondrial Deficiency Treatment
Fortunately, we live in an age of discovery. Because we have begun to characterize both the diseases and the particular metabolic complexes involved with a disease, cures maybe within reach. Understanding the mechanisms involved in the SDH reaction may permit repairing of damaged proteins. Another application could be to synthesize drugs that can substitute a dysfunctional enzyme. The defective enzyme could be by-passed if molecules with similar oxidation states can be introduced into the mitochondrial system to carry electrons to the next enzyme in the electron transport chain.
Aging and SDH
An increase of SDH activity has been observed in aging individuals (Shoffner 2000). By knowing how the reaction proceeds, inhibitors could be introduced to decrease reactivity. An inhibitor with a redox potential between the fourth heme and the FAD of SDH could potentially halt the electron transfer. Another mechanistic alteration could involve the charged bent helix linker and preventing its hinge-door function. A number of changes could result in a decrease in function and, therefore, a retardation of the aging process.
Treatment of Obesity and SDH
Weight loss has been correlated with increases in SDH activity (Kern et al 1999). By regulating SDH, weight loss might also be regulated, which could lead to benefits for people struggling with extreme obesity. If the mechanism is understood, drugs can be tailored to enhance the SDH reaction. If the enzyme were in an environment that alters the tertiary structure so that the electrons could shoot down the heme-wire faster, an increase in activity might occur. Drugs, however, may not be the answer to obesity. Understanding this mechanism may provide insight into the natural tendency for individuals to be skinny or large. If we understand the relationship between SDH activity and weight loss, treatments besides medication might be developed.