Madhavi Bhatia, NIPER Guwahati
Mitochondria and the pathological events surrounding it:
Mitochondria, also known as the powerhouse of a cell, approximately generates about 95 % of the cellular adenosine triphosphate (ATP) through oxidative phosphorylation. Mitochondria play a crucial role in the regulation of cellular physiology and pathological mechanisms which include metabolic control, ATP generation, immune response, signal transduction, and apoptosis. However, mitochondrial dynamics and function may change due to some pathological reasons during disease development which may affect the overall metabolism of the body. Mitochondria have been recognized as unintended drug targets of many therapeutic agents that might damage mitochondria leading to changes in the mitochondrial morphology and function. For example- troglitazone, a drug of the thiazolidinedione class of antidiabetic drugs was withdrawn from the market in 2000 due to lethal hepatotoxicity caused by the off-target effect on the electron transport chain of mitochondria.
A database to solve the problem:
To understand the pharmacological and toxicological mechanisms that influence mitochondrial toxicity, a database is required which is capable of integrating information about mitochondrial toxicity and record data acquired by the measurements of the mitochondrial functions. The MitoTox database is a drug database that is known to combine general pharmaceutical information as well as experimental data on the drugs. Chemical properties, clinical applications, bioactivity, toxicity, side–effects information, and ATC code about a particular drug were obtained from DrugBank, Uniprot, PubChem, and SIDER databases. The ingenuity pathway analysis database was used to find the correlation between mitochondrial function and target molecules. The database currently has about 1400 drugs/compounds in total. All of these compounds have been tested and have shown enough evidence of mitochondrial toxicity. These are then further classified into 77 categories of mitochondrial toxicity mechanisms.
Working of the MitoTox:
Mitochondrial toxicities can arise from different mechanisms they are divided into 8 categories depending on their functionality – organization of mitochondria, the function of mitochondria, movement of mitochondria, alteration in transmembrane potential, cell death, oxidative stress, mitochondrial DNA, and metabolic-related signalling pathway. These are further divided into subcategories according to the corresponding toxicity mechanism. For example: in the category of transmembrane potential mechanism, uncoupling or modulating transport of ions, inhibiting ETC might be the mechanisms that affect the mitochondrial membrane potential. Mitochondrial toxicity-related targets include transporters or carriers on the membrane, mitochondrial DNA replication machinery, RNAs, mitochondrial enzymes present in the matrix, protein synthesis, etc. These targets can also be classified on the basis of location –intermembrane space (IMS), outer mitochondrial membrane (OMM), inner mitochondrial membrane(IMM), and mitochondrial matrix. The drug targets related to mitochondria and metabolism are cross-referenced and linked by toxin-target association.
Respiration rate and cellular ATP content in the body are important indicators of mitochondrial health. Various screening assays for mitochondrial toxicity include- measurement of mitochondrial oxygen consumption, reactive oxygen species, mitochondrial membrane potential, and cellular ATP content. Many of these functional assays are applied to high-throughput screening for mitochondrial toxicity. Statistics methods such as Fischer exact test could be used to define an association between mitochondrial toxicity and side effects. Mitochondrial stress can also be evaluated on the basis of parameters of mitochondrial dynamics, ROS production, and permeability transition of which oxidative stress plays an important role in mitochondrial toxicity. ROS are the side-products of mitochondrial electron transport and also regulators of cell signalling during differentiation, growth, and metabolism. Excessive levels of ROS might cause oxidative damage and cell death. Many chemical compounds and environmental pollutants are also involved in the generation of reactive species and oxidative stress thus affecting mitochondrial and cellular functions. Drugs that would significantly change the mitochondrial membrane potential and oxygen consumption profiles (OCR) profiles of mitochondria are included within the MitoTox database. These are labelled as positive and negative entries based upon the experimental criteria. Thus, the MitoTox database, an open access database will help to develop and improve detection and screening procedures for mitochondrial toxicity.
Future prospects:
MitoTox will help us in advancing our understanding regarding mitochondrial-associated toxicity and also provide new possibilities for the early diagnosis of mitochondrial diseases. Understanding the mitochondrial toxicity of drugs would help in the development of drugs that target mitochondria to treat some diseases.
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Source:
Lin, Y.-T., Lin, K.-H., Huang, C.-J., & Wei, A.-C. (2021). MitoTox: A comprehensive mitochondrial toxicity database. BMC Bioinformatics, 22(10), 369. https://doi.org/10.1186/s12859-021-04285-3
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About the author– Madhavi Bhatia is currently pursuing a Master of Science degree in Pharmaceutical Biotechnology from NIPER, Guwahati. Her area of interest lies in understanding the role of gene mutation in the development of various diseases and developing a treatment for such diseases.
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