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  1. National Center for Toxicological Research

MitoChip: An NCTR-Developed Mitochondrial Research Tool

Comprehensive knowledge and resources on mitochondrial function, mitochondrial injury, and mitochondrial toxicity

Scientific Information About MitoChip
 

Features of MitoChip Research Tool 
 

NCTR Publications Related to MitoChip
 

MitoChip Contact Information

This NCTR MitoChip webpage is created to provide comprehensive knowledge and resources on mitochondrial function, mitochondrial injury, and mitchondrial toxicity, while also reporting progress on NCTR’s contributions to mitochondrial research. On this page you will find links to comprehensive gene information for five species and a listing of NCTR publications on understanding the mechanism of mitochondrial toxicity and development of biomarkers to predict toxicity. Check back often for new information about the NCTR-developed MitoChip ...

The human body is made up of trillions of cells (basic unit of life). Each cell contains different organelles that perform specific functions. Mitochondrion is an organelle that plays a critical role in the survival and function of cells. Damage to mitochondria can lead to diseases, such as Alzheimer’s disease, diabetes, and obesity. Because there are FDA-regulated drugs (e.g., anti-HIV drugs, anti-cancer drugs) that cause mitochondrial injury, it is important to understand the mechanism of mitochondrial injury and to develop measures for prevention of mitochondrial damage.

Under the leadership of Dr. Varsha Desai, NCTR scientists have developed MitoChips for different species, which contain all the mitochondria-related genes on a chip (glass slide).  Mitochondria-related genes are regions on DNA (deoxyribonucleic acid), which encode proteins that are important for mitochondrial structure and function. MitoChip is a tool to evaluate the change in mitochondrial gene expression in response to various agents including drugs. NCTR has published several papers illustrating the mechanism of mitochondrial toxicity in response to different drugs in the mouse and rat. Additionally, NCTR scientists have developed MitoChips for human and non-human primates for better prediction of toxicity, in addition to our findings in rodents.  Read more scientific information about MitoChip.

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For more information or to provide suggestions, please contact:

Vikrant Vijay, BVSc, MVSc, Ph.D.

Personalized Medicine Branch, Division of Systems Biology
National Center for Toxicological Research
E-mail: Vikrant.Vijay@fda.hhs.gov
Phone: 870-543-7525

Varsha Desai, Ph.D.

Personalized Medicine Branch, Division of Systems Biology
National Center for Toxicological Research
E-mail: Varsha.Desai@fda.hhs.gov
Phone: 870-543-7631

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Scientific Information About MitoChip

Mitochondria generate most of the energy (>90%) for all essential processes in eukaryotic cells. This key function of mitochondria is executed via oxidative phosphorylation, which is composed of four complexes (I through IV) of the electron transport chain that couple with complex V to produce energy as ATP (Adenosine Triphosphate). In addition to the prime function of energy production, these cellular organelles are involved in fatty acid β-oxidation, the citric acid cycle (TCA cycle), heme and iron-sulfur cluster assembly, amino acids, pyrimidine, and steroid synthesis, and calcium and iron homeostasis. While mitochondrial energy is vital for the survival of cells, these organelles also play an important role in the execution of apoptosis (programmed cell death), a process that serves as a major defense mechanism to remove unwanted and potentially dangerous cells. Furthermore, mitochondria are major sites of production of reactive oxygen species. Together, these functions highlight the critical role of mitochondria in the life and death of cells. One of the unique features of mitochondria is that they contain their own small, circular DNA (deoxyribonucleic acid) and independent machinery of ribosomal and transfer RNAs (ribonucleic acid) and ribosomes for synthesis of 13 proteins encoded by the mitochondrial DNA essential for oxidative phosphorylation. In addition, 22 tRNA and 2 rRNA are also encoded by mitochondrial DNA. The rest of approximately 1,900 proteins (in humans) required for the performance of various mitochondrial functions are encoded by the nuclear DNA. A precise coordination between mitochondrial and nuclear DNA is, therefore, crucial for optimum mitochondrial function.

Organs, such as the heart, brain, liver, skeletal muscle, kidney, and lungs with high energy demand are significantly dependent on mitochondrial energy for efficient performance. Impairment in mitochondrial function, therefore, can be injurious to these organs. Mitochondrial dysfunction has been implicated in the toxicities of certain diseases and many drugs. Altered mitochondrial activity has been indicated in a number of degenerative diseases including, cardiovascular diseases, neurodegenerative diseases (Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis), and metabolic disorders (obesity, Type-2 diabetes mellitus). It is also becoming increasingly evident that mitochondria are a major target of many therapeutic drugs, such as anti-HIV drugs, anti-cancer drugs, and environmental toxins that can alter its function through different mechanisms. Drugs can cause mitochondrial disruption by altering the gene expression and/or function of proteins involved in energy production, mitochondrial biogenesis, and mitochondrial DNA replication, as well as inducing oxidative stress. Consequently, this can lead to cellular injury with further manifestations of overt organ toxicities.

It is still an enigma if mitochondrial dysfunction is a cause or consequence of degenerative diseases or drug-induced toxicities. Despite utilization of a number of molecular and biochemical technologies, the precise role of mitochondria in the development or progression of degenerative diseases or drug-induced toxicities is still not fully understood. This may partly be due to investigation of specific aspects of the mitochondrial role, in contrast to simultaneous evaluation of multiple facets of mitochondrial function to understand the complexity of these organelles and their role in the development or progression of drug-induced toxicities or diseases.

To address this, a mouse mitochondria-specific oligonucleotide microarray (MitoChip) was developed at the FDA’s National Center for Toxicological Research in 2007 [1, 2, 3]. This comprehensive genomic tool facilitated simultaneous measurement of the expression of 542 genes associated with mitochondrial structure and function to help define mitochondrial activity during various toxic insults. Unlike commercially available high-density gene expression microarrays, the mouse MitoChip is unique because it consists of both mitochondrial and nuclear genes-encoding mitochondrial proteins to obtain important insights into the interaction between mitochondrial and nuclear genomes during disease or toxic conditions. The utility of this genomic tool in understanding the mechanism of mitochondrial dysfunction in different tissues has been demonstrated in mouse models treated with anti-HIV drugs (zidovudine [2, 4, 5], lamivudine[2, 4]), anti-cancer drugs (flutamide [6], cisplatin [7]), and environmental toxins (acrylamide [8], usnic acid [9]) in collaborative studies with NIEHS’ National Toxicological Program and academia. Moreover, mouse MitoChip was capable of detecting subtle transcriptional changes in mitochondria prior to overt drug toxicity [4, 9], suggesting its potential in identifying gene expression patterns (biomarkers) for predicting early stages of mitochondrial toxicity that may be valuable in risk assessment. An ontology approach is employed in interpreting mitochondrial gene expression data using in-house developed statistical program and custom gene ontology (GO) annotations [10, 11]. This approach will help identify differentially expressed mitochondrial genes, which may be responsible for the development of certain diseases and drug-induced organ toxicities and shed light on the pathways underlying diseases and drug toxicities.

The success of the mouse MitoChip in defining novel mechanisms of drug-induced toxicities encouraged the upgrade of the mouse MitoChip by increasing the number of mitochondria-related genes (809) and development of the rat MitoChip on a commercial platform (Agilent Technologies, Santa Clara, CA). The use of the rat MitoChip demonstrated a likely involvement of mitochondria in sex-based differential cardiotoxicity induced by an anti-cancer drug, doxorubicin, in spontaneously hypertensive rats in a collaborative study with Dr. Rao at the FDA’s Center for Drug Evaluation and Research [12]. Additionally, MitoChip gene libraries have been created for non-human primates (Macaca mulatta (Rhesus macaque) and Macaca fascicularis (crab-eating/cynomolgus macaque) and humans for development on the Agilent platform. Use of MitoChips in different mammalian species will enhance our understanding of the mechanisms underlying species-specific differences in drug-induced toxicities and disease susceptibilities associated with mitochondrial dysfunction. This knowledge will be valuable in the development of predictive biomarkers of early events of drug toxicity or onset of diseases, which may help in bridging the gap between non-clinical and clinical research. 
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Features of MitoChip 

Species

MitoChip Ready for Use

Nuclear-Encoded Genes

Mitochondria-Encoded Genes

Housekeeping Genes

Total Genes

Chip Format

Mouse

(Mus musculus)

Yes 778 31 20 829 8 x 15k

Rat

(Rattus norvegicus)

Yes 721 33 16 770 8 x 15k

Rhesus

(Macaca mulatta)

In process 1470 37 19 1526 8 x 15k

Cynomolgus

(Macaca fascicularis)

In process 1380 37 14 1431 8 x 60k

Human

(Homo sapiens)

In process 1899 37 20 1956 8 x 60k

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NCTR Publications Related to MitoChip
 

  1. Desai V., Fuscoe J. (2007) Transcriptional profiling for Understanding the Basis of Mitochondrial Involvement in Disease and Toxicity Using the Mitochondria-specific MitoChip.  Mutat. Res., 616(1-2): 210-212.

  2. Desai V., Lee T., Delongchamp R., Moland C., Branham W., Fuscoe J., Leakey J. (2007) Development of mitochondria-specific mouse oligonucleotide microarray and validation of data by real-time PCR.  Mitochondrion, 7(5): 322-329.

  3. Delongchamp R., Velasco C., Desai V., Lee T., Fuscoe J. (2008) Designing toxicogenomics studies that use DNA array technology.  Bioinform. Biol. Insights, 2: 317-328.

  4. Desai V., Lee T., Delongchamp R., Leakey J., Lewis S., Lee F., Moland C., Branham W., Fuscoe J. (2008)  Nucleoside reverse transcriptase inhibitors (NRTIs)-induced expression profile of mitochondria-related genes in the mouse liver.  Mitochondrion, 8(2): 181-195.

  5. Lee T., Desai V., Velasco C., Reis R., Delongchamp R. (2008) Testing for treatment effects on gene ontology. BMC Bioinformatics, 9 (Suppl. 9):S20.

  6. Desai V., Lee T., Moland C., Branham W., Von Tungeln L., Beland F., Fuscoe J. (2009) Effect of short-term exposure to zidovudine on the expression of mitochondria-related genes in skeletal muscle of neonatal mice.  Mitochondrion, 9(1): 9-16.

  7. Joseph A., Lee T., Moland C., Branham W., Fuscoe J., Leakey J., Allaben W., Lewis S., Ali, A., Desai V. (2009)  Effect of usnic acid on mitochondrial functions as measured by mitochondria-specific oligonucleotide microarray in liver of B6C3F1 mice.  Mitochondrion, 9(2): 149-158.

  8. Kashimshetty R., Desai V., Kale V., Lee T., Moland C., Branham W., New L., Chan E., Younis H., Boelsterli U. (2009) Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity.  Toxicol. Appl. Pharm.,  238(2): 150-159.

  9. Li S., Nagothu K., Desai V., Lee T., Branham W., Moland C., Megyesi J., Crew M, Portilla D. (2009) Transgenic expression of proximal tubule peroxisome proliferator-activated receptor-alpha in mice confers protection during acute kidney injury. Kidney Int., 76(10): 1049-1062.

  10. Desai V. (2011) Mitochondria-specific mouse gene array and its application in toxicogenomics.  Handbook of Systems Toxicology, Eds. Drs. Saura Sahu and Daniel Casciano, John Wiley and Sons Ltd., U.K., Vol. 1, pp 125-146.

  11. Lee T., Manjanatha M., Aidoo A., Moland C., Branham W., Fuscoe J., Ali A., Desai V. (2012)  Expression Analysis of Hepatic Mitochondria-related Genes in Mice Exposed to  Acrylamide and Glycidamide.  J. Toxicol. Environ. Health A, 75(6): 324-339.

  12. Gonzalez Y., Pokrzywinski K., Rosen E., Mog S., Aryal B., Chehab L., Vijay V., Moland C., Desai V., Dickey J., Rao V. (2015) Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats. Cancer Chemother. Pharmacol., 76(3):447-459.

  13. Vijay V., Moland L., Han T., Fuscoe C., Lee T., Herman H., Jenkins R., Lewis M., Cummings A., Gao Y., Cao Z., Yu R., Desai G. (2016) Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice. Toxicol Appl Pharmacol. 295:68-84.

  14. Desai V. and Jenkins G. (2017) MitoChip: A transcriptomics tool for elucidation of mechanisms of mitochondrial toxicity. In Drug-Induced Mitochondrial Dysfunction: Progress Towards the Clinic, 2nd Edition. Eds. Drs. Yvonne Will and James A. Dykens, John Wiley and Sons Inc. U.S.A., pp 275-293.

  15. Sajja K., Kaisar A., Vijay V., Desai G., Prasad S., Cucullo L. (2018) In Vitro Modulation of Redox and Metabolism Interplay at the Brain Vascular Endothelium: Genomic and Proteomic Profiles of Sulforaphane Activity. Sci Rep. 8(1):12708.

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