Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins
Marina A Schwab1, Sven W Sauer, Jürgen G Okun
1Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany.
The Biochemical Journal
|May 12, 2006
Summary
Propionyl-CoA, a metabolite in propionic acidurias, inhibits key mitochondrial enzymes like pyruvate dehydrogenase complex (PDHc). This toxic metabolite contributes to severe mitochondrial dysfunction observed in patients.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Disorders
Background:
- Inherited disorders of propionate metabolism, such as propionic and methylmalonic acidurias, involve the accumulation of propionyl-CoA.
- Mitochondrial dysfunction is a key factor in the acute metabolic crises associated with these disorders.
Observation:
- Propionyl-CoA uncompetitively inhibits the pyruvate dehydrogenase complex (PDHc) with similar potency to acetyl-CoA.
- Propionyl-CoA also inhibits respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex.
- In vitro studies showed chain-length specificity for PDHc inhibition by CoA esters, with non-esterified fatty acids having no inhibitory effect.
Findings:
- Muscle biopsies from propionic aciduria patients revealed severely compromised oxidative phosphorylation.
- Patients exhibited decreased expression of respiratory chain complexes I-IV and reduced mitochondrial DNA content.
- Significant ultrastructural mitochondrial abnormalities were observed, confirming severe mitochondrial dysfunction.
Implications:
- Toxic metabolites, particularly propionyl-CoA, are implicated in the pathogenesis of inherited propionate metabolism disorders.
- The findings suggest mechanistic similarities between propionate toxicity in humans and microorganisms.
- This research supports targeting propionyl-CoA toxicity as a therapeutic strategy for propionic acidurias.
Related Concept Videos
01:48ATP Synthase: Mechanism
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP...
01:30The Electron Transport Chain
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
01:46Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
01:19Translocation of Proteins into the Mitochondria
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:15Pyruvate Oxidation
After glycolysis, the charged pyruvate molecules enter the mitochondria via active transport and undergo three enzymatic reactions. These reactions ensure that pyruvate can enter the next metabolic pathway so that energy stored in the pyruvate molecules can be harnessed by the cells.
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
01:37Mitochondria
Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...