When considering metabolism, what may first come to mind is the breaking down of dietary components to make energy for us to perform our daily tasks. However, metabolism is an intricate, complicated process that involves many chemical reactions in the body that modify, break down, store, and use a variety of molecules. Correct functioning of these reactions is important for all body systems and the ease of our daily actions. When these processes go wrong, severe consequences may occur.
Diabetes is a result of some of the most common defects in the body’s ability to use energy. Broadly, this condition involves defects in systemic metabolism due to progressive dysfunction in the pancreas’ ability to create insulin, a hormone involved in regulating blood glucose levels. However, errors in metabolism can also occur at the cellular level. Metabolic defects often stem from genetic mutations that can impair breakdown, accumulation and usage of components involved in cellular function.
Gaucher’s disease is an important example of such genetic mutations. It is an autosomal recessive condition in which individuals have a mutation in the gene GBA that is responsible for creating a protein involved in breaking down an important component of the cell membrane, called glycosphingolipids (GSLs). Therefore, errors in this protein lead to accumulation of GSLs in cells, often in a type of immune cell called macrophages. This accumulation in macrophages can lead to heterogeneous clinical presentation, affecting a variety of organ systems. One type of Gaucher’s disease can lead to enlarged spleen and liver, bone disease, errors in blood coagulation and sometimes lung, renal and cardiac dysfunction. Gaucher disease can also be fatal a few weeks after birth when the central nervous system is affected. Treatment involves rendering the protein functional in macrophages infused into the patient, using synthesized protein, or reducing the synthesis of the GSLs.
Another genetic metabolic disorder is hemochromatosis which involves an excess of iron in the body that is often caused by defects in proteins responsible for acquiring or regulating iron. Iron is needed for the normal function of cells, but excess amounts can be toxic and lead to free-radical induced tissue damage that causes clinical disease. The most common mutation is in one particular locus of the homeostatic iron regulator (HFE) gene. Despite how common this mutation is in hemochromatosis, there is still great variety in disease severity. Symptoms appear gradually as individuals accumulate iron over time and can be particularly severe in the liver, joints, anterior pituitary and pancreas. It can therefore lead to liver dysfunction, cardiac issues, diabetes mellitus, etc. Treatment involves taking blood from patients at regular intervals to reduce the amount of iron in the body.
Finally, an analysis of metabolism cannot be completed without a consideration of the powerhouse of the cell, mitochondria. The possible errors in mitochondrial metabolism are legion and have been grouped into a general classification of ‘mitochondrial disorders’ that are associated with a vast range of conditions including cardiovascular disorders, neurodegenerative disorders, cancer, obesity and many more. Most often, these disorders present in the body in tissues with high energy demand including the central nervous system, heart muscles, and skeletal muscles. Symptoms vary depending on the tissue of presentation. These disorders result from mutations in genes encoded within the mitochondria itself, or mitochondrial genes encoded in the nucleus.
Overall, metabolism is an extraordinarily complicated, diverse and vital series of reactions in the body that allow for proper functioning of cells. However, this complexity introduces many areas for errors and dysfunction that can lead to severe, sometimes fatal clinical effects.
- Kandola. Metabolic disorders: Types, causes, and symptoms. Medical News Today
- https://www.medicalnewstoday.com/articles/metabolic-disorders (2021).
- Grabowski, G. A. Phenotype, diagnosis, and treatment of Gaucher’s disease. The Lancet372, 1263–1271 (2008).
- Aerts, J. M. F. G. et al.Glycosphingolipids and lysosomal storage disorders as illustrated by gaucher disease. Current Opinion in Chemical Biology53, 204–215 (2019).
- Anderson, G. J. & Bardou-Jacquet, E. Revisiting hemochromatosis: genetic vs. phenotypic manifestations. Ann Transl Med9, 731 (2021).
- Khan, N. A., Govindaraj, P., Meena, A. K. & Thangaraj, K. Mitochondrial disorders: Challenges in diagnosis & treatment. Indian J Med Res141, 13–26 (2015).
- DiMauro, S. & Garone, C. Historical perspective on mitochondrial medicine. Developmental Disabilities Research Reviews16, 106–113 (2010).
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