Sundararajan

Venkatesh Sundararajan

Contact

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Phone
304-293-9785
Fax
304-293-3850
Address
Office: 3065, HSC North, Floor 3
Lab: 3054, HSC North, Floor 3
Additions & Corrections?

Positions

Associate Professor

Organization:
School of Medicine
Classification:
Faculty

Publications

Google Scholar: https://scholar.google.com/citations?user=YIJxFQoAAAAJ&hl=en 

  1. Muthu S, Sukumaran V and Venkatesh S. Editorial: Understanding Molecular Mechanisms in Diabetic Cardiomyopathy (DCM). Front. Cardiovasc. Med. 2022;9:965650.
     
  2. Muthu S and Venkatesh S. A Commentary on “PI3K- α/mTOR/BRD4 inhibitor alone or in combination with other anti-virals blocks replication of SARS-CoV-2 and its variants of concern including Delta and Omicron”. Clin. Transl. Disc. 2022;2:e87
     
  3. Lee J, Pandey AK, Venkatesh S, Thilagavathi J, Honda T, Singh K, Suzuki CK. Inhibition of mitochondrial LonP1 protease by allosteric blockade of ATP -binding and -hydrolysis via CDDO and its derivatives. J Biol Chem. 2022 Feb 10:101719. doi: 10.1016/j.jbc.2022.101719.
     
  4. Sukumaran V, Gurusamy N, Yalcin HC, Venkatesh S. Understanding Diabetes Induced cardiomyopathy from the perspective of Renin Angiotensin Aldosterone System (RAAS) and associated co-factors. Pflügers Archiv: European Journal of Physiology  Pflügers Archiv - European Journal of Physiology 2022; 474, 63–81.
     
  5. Srinivasan K, Pandey AK, Livingston A, Venkatesh S. Roles of host mitochondria in the development of COVID-19 pathology: Could mitochondria be a potential therapeutic target? Mol Biomed. 2021 Nov 23;2:38.
     
  6. Oka SI, Byun J, Huang CY, Imai N, Ralda GE, Zhai P, Xu X, Kashyap SS, Warren JS, Maschek JA, Tippetts TS, Tong M, Venkatesh S, Ikeda Y, Mizushima W, Kashihara T, Sadoshima J. Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy. Circ Res. 2021 Jun 25;129(1):114-130.
     
  7. Venkatesh S*, Baljinnyam E*, Tong M, Kashihara T, Yan L, Liu T, Li H, Xie L, Nakamura M, Oka S, Suzuki CK, Fraidenraich D, and Sadoshima J (2020). Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells. Am J Physiol Regul Integr Comp Physiol . 2021 Apr 1;320(4):R547-R562. (*First authors)
     
  8. S. Venkatesh* and C.K. Suzuki*, Cell stress management by the mitochondrial LonP1 protease - Insights into mitigating developmental, oncogenic and cardiac stress, Mitochondrion 51 (2019) 46-61. (* Corresponding authors).
     
  9. Venkatesh S*, Li M, Saito T, Tong M, Rashed E, Mareedu S, et al. Suzuki CK * (2019). Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo. J Mol Cell Cardiol 128: 38-50. (* Corresponding authors).
     
  10. Venkatesh S, Chauhan M, Suzuki C, & Chauhan N (2019). Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis. J Vis Exp 19;(145).
     
  11. Jeyapal GP, Krishnasamy R, Suzuki CK, Venkatesh S, & Chandrasekar MJN (2019). In-silico design and synthesis of N9-substituted beta-Carbolines as PLK-1 inhibitors and their in-vitro/in-vivo tumor suppressing evaluation. Bioorg Chem 88: 102913.
     
  12. Nimmo GAM*, Venkatesh S*, Pandey AK*, Marshall CR, Hazrati LN, Blaser S, et al. (2019). Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. Hum Mol Genet 28: 290-306. (*First authors)
     
  13. Pandey AK, & Venkatesh S (2019). Protein quality control at the interface of endoplasmic reticulum and mitochondria by Lon protease. Br J Pharmacol 176: 505-507 (* Corresponding author).
     
  14. King GA, Hashemi Shabestari M, Taris KH, Pandey AK, Venkatesh S, Thilagavathi J, et al. (2018). Acetylation and phosphorylation of human TFAM regulate TFAM-DNA interactions via contrasting mechanisms. Nucleic Acids Res 46: 3633-3642.
     
  15. Baljinnyam E, Venkatesh S, Gordan R, Mareedu S, Zhang J, Xie LH, et al. (2017). Effect of densely ionizing radiation on cardiomyocyte differentiation from human-induced pluripotent stem cells. Physiol Rep 5.
     
  16. Venkatesh S, & Suzuki CK (2017). HSP60 Takes a Hit: Inhibition of Mitochondrial Protein Folding. Cell Chem Biol 24: 543-545.
     
  17. Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, et al. (2015). CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet 96: 121-135.
     
  18. Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, et al. (2013). Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol Cell 49: 121-132.
     
  19. Thilagavathi J, Kumar M, Mishra SS, Venkatesh S, Kumar R, & Dada R (2013). Analysis of sperm telomere length in men with idiopathic infertility. Arch Gynecol Obstet 287: 803-807.
     
  20. Bernstein SH*, Venkatesh S*, Li M, Lee J, Lu B, Hilchey SP, Morse KM, Metcalfe HM, Skalska J, Andreeff M, Brookes PS, and Suzuki CK. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 119: 3321-3329, 2012. (* First authors)
     
  21. Thilagavathi J, Venkatesh S, & Dada R (2013). Telomere length in reproduction. Andrologia 45: 289-304.
     
  22. Venkatesh S, Lee J, Singh K, Lee I, & Suzuki CK (2012). Multitasking in the mitochondrion by the ATP-dependent Lon protease. Biochim Biophys Acta 1823: 56-66.
     
  23. Kumar M, Pathak D, Venkatesh S, Kriplani A, Ammini AC, & Dada R (2012). Chromosomal abnormalities & oxidative stress in women with premature ovarian failure (POF). Indian J Med Res 135: 92-97.
     
  24.  Thilagavathi J, Venkatesh S, Kumar R, & Dada R (2012). Segregation of sperm subpopulations in normozoospermic infertile men. Syst Biol Reprod Med 58: 313-318.
     
  25. Venkatesh S, Shamsi MB, Deka D, Saxena V, Kumar R, & Dada R (2011). Clinical implications of oxidative stress & sperm DNA damage in normozoospermic infertile men. Indian J Med Res 134: 396-398.
     
  26. Venkatesh S, Shamsi MB, Dudeja S, Kumar R, & Dada R (2011). Reactive oxygen species measurement in neat and washed semen: comparative analysis and its significance in male infertility assessment. Arch Gynecol Obstet 283: 121-126.
     
  27. Dada R, Mahfouz RZ, Kumar R, Venkatesh S, Shamsi MB, Agarwal A, et al. (2011). A comprehensive work up for an asthenozoospermic man with repeated intracytoplasmic sperm injection (ICSI) failure. Andrologia 43: 368-372.
     
  28. Kumar K, Venkatesh S, Sharma PR, Tiwari PK, & Dada R (2011). DAZL 260A > G and MTHFR 677C > T variants in sperm DNA of infertile Indian men. Indian J Biochem Biophys 48: 422-426.
     
  29. Kumar R, Saxena V, Shamsi MB, Venkatesh S, & Dada R (2011). Herbo-mineral supplementation in men with idiopathic oligoasthenoteratospermia : A double blind randomized placebo-controlled trial. Indian J Urol 27: 357-362.
     
  30. Shamsi MB, Venkatesh S, Pathak D, Deka D, & Dada R (2011). Sperm DNA damage & oxidative stress in recurrent spontaneous abortion (RSA). Indian J Med Res 133: 550-551.
     
  31. Venkatesh S, Singh A, Shamsi MB, Thilagavathi J, Kumar R, Mitra DK, et al. (2011). Clinical significance of sperm DNA damage threshold value in the assessment of male infertility. Reprod Sci 18: 1005-1013.
     
  32. Venkatesh S, Thilagavathi J, Kumar K, Deka D, Talwar P, & Dada R (2011). Cytogenetic, Y chromosome microdeletion, sperm chromatin and oxidative stress analysis in male partners of couples experiencing recurrent spontaneous abortions. Arch Gynecol Obstet 284: 1577-1584.
     
  33. Venkatesh S, Kumar R, Deka D, Deecaraman M, & Dada R (2011). Analysis of sperm nuclear protein gene polymorphisms and DNA integrity in infertile men. Syst Biol Reprod Med 57: 124-132.
     
  34. Venkatesh S, & Dada R (2011). An evolutionary insight into mutation of ATPase6 gene in primary ovarian insufficiency. Arch Gynecol Obstet 284: 251-252.
     
  35. Shamsi MB, Venkatesh S, Kumar R, Gupta NP, Malhotra N, Singh N, et al. (2010a). Antioxidant levels in blood and seminal plasma and their impact on sperm parameters in infertile men. Indian J Biochem Biophys 47: 38-43.
     
  36. Shamsi MB, Venkatesh S, Tanwar M, Singh G, Mukherjee S, Malhotra N, et al. (2010b). Comet assay: a prognostic tool for DNA integrity assessment in infertile men opting for assisted reproduction. Indian J Med Res 131: 675-681.
     
  37. Dada R, Venkatesh S, Kumar K, & Shamsi MB (2010). Re: Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate: M. Smit, J. C. Romijn, M. W. Wildhagen, J. L. Veldhoven, R. F. Weber and G. R. Dohle J Urol 2010; 183: 270-274. J Urol 184: 1577; author reply 1578.
     
  38. Dada R, Shamsi MB, Venkatesh S, Gupta NP, & Kumar R (2010). Attenuation of oxidative stress & DNA damage in varicocelectomy: implications in infertility management. Indian J Med Res 132: 728-730.
     
  39. Venkatesh S, & Dada R (2010). Acridine orange binding to RNA interferes DNA fragmentation index calculation in sperm chromatin structure assay. Fertil Steril 94: e37, author reply e38.
     
  40. Venkatesh S, Kumar M, Sharma A, Kriplani A, Ammini AC, Talwar P, et al. (2010). Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency. Arch Gynecol Obstet 282: 313-318.
     
  41. Kumar R, Venkatesh S, Kumar M, Tanwar M, Shasmsi MB, Kumar R, et al. (2009). Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men. Indian J Biochem Biophys 46: 172-177.
     
  42. Venkatesh S, Deecaraman M, Kumar R, Shamsi MB, & Dada R (2009). Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mtDNA) mutations in male infertility. Indian J Med Res 129: 127-137.
     
  43. Shamsi MB, Venkatesh S, Tanwar M, Talwar P, Sharma RK, Dhawan A, et al. (2009). DNA integrity and semen quality in men with low seminal antioxidant levels. Mutat Res 665: 29-36.
     
  44. Venkatesh S, Riyaz AM, Shamsi MB, Kumar R, Gupta NP, Mittal S, et al. (2009). Clinical significance of reactive oxygen species in semen of infertile Indian men. Andrologia 41: 251-256.
     
  45. Venkatesh S, Shamsi MB, & Dada R (2009). Re: Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele: S.-S. Chen, W. J. Huang, L. S. Chang and Y.-H. Wei J Urol 2008; 179: 639-642. J Urol 181: 1964-1965; author reply 1965-1966.
     
  46. Dada R, Kumar R, Shamsi MB, Tanwar M, Pathak D, Venkatesh S, et al. (2008). Genetic screening in couples experiencing recurrent assisted procreation failure. Indian J Biochem Biophys 45: 116-12.
     
Publications Link

Research Interests

Despite advanced medical technologies, heart disease and cancer are still the leading cause of death in humans. Interestingly, mitochondria are dysregulated in these diseases. This is because mitochondria are unique cellular organelles that not only produce energy on demand but also emerge as an essential organelle that regulates various functions such as calcium homeostasis, cellular signaling, apoptosis, nucleotide and metabolic levels, and steroid and heme biosynthesis. Therefore, the primary focus of out laboratory is to understand how mitochondria contribute to the pathology of these diseases. One aspect of this is we study the mechanisms of mitochondrial protein quality (MPQC), currently focusing on mitochondrial Lon protease (LonP1), the major mitochondrial ATP-dependent protease, to develop novel therapeutic tools and strategies targeting heart disease and cancer.

 

MAJOR PROJECTS UNDERWAY

•   In one of the major projects, we are currently working on understanding the role of mitochondrial LonP1 in cardiac function and protection. Here, we focus on myocardial Ischemia-reperfusion (IR) injury, which is a significant challenge in treating myocardial infarction (MI), the leading cause of death worldwide. Mitochondrial reactive oxygen species (mtROS) generated by electron transport chain (ETC) Complex-I are the principal mediators of IR injury. Excess mtROS generated during early IR triggers vicious cycles of free radical production promoting cardiomyocyte death. Therefore, understanding the early molecular events of reperfusion will provide new targets for developing novel interventions for limiting cardiac injury. Our published findings show that LonP1- a major mitochondrial stress response protease mitigates oxidative stress-induced damage during early IR; therefore, we believe that LonP1 could be a promising target for attenuating reperfusion injury. Our long-term goal is to leverage the mitochondrial protein quality control (MPQC) mechanisms of LonP1 as a pivotal point in developing therapeutic strategies such as delivering LonP1 to the heart and/or activating LonP1 by small molecules for mitigating IR injury and post-MI- heart failure.

 

•    In another breakthrough project, we are investigating the role of mitochondria in contributing to doxorubicin (DOX) induced cardiomyopathy. DOX is one of the first-line chemotherapeutic agents against various cancers and acts by interfering with DNA replication. But, its action on non-replicating cardiomyocytes causing cardiotoxicity is largely unknown. Thus, this lack of understanding limits identifying therapeutic strategies to treat DOX-induced cardiomyopathy. In this project, we hypothesize that DOX accumulates within mitochondria, binds mtDNA, and reduces mitochondrial biogenesis, thereby inducing progressive mitochondrial and cardiac dysfunction. Therefore, understanding the exact mechanisms of DOX-mediated heart failure will help to identify novel strategies to develop therapeutic applications. We are also investigating whether LonP1 plays any role in protecting against DOX-mediated cardiotoxicity. In addition, in clinical collaboration with Dr. Brijesh Patel, a cardio oncologist at WVU Heart and Vascular Institute, we aim to potentially develop a novel, affordable, and clinically relevant means to predict patient outcomes before DOX treatment.

 

•    In this cancer project, we investigate the role of mitochondrial DNA in tumor progression. Specifically, in this project, we focus on cervical cancer, the fourth most common cause of cancer in women. ThIn a clinical collaboration with Dr. Mark Einstein, Rutgers-New Jersey Medical School, our new data from the clinical human cervical samples indicate that the advancement in cervical cancer stages is associated with decreased mtDNA content. We also found that mtDNA regulates p53 function in cervical cancer, contributing to chemotherapeutic resistance, which will be explored in this project. The outcome will also have a better implication in developing approaches to treating other HPV-induced cancers such as head, neck, and anal cancers.

Grants and Research

FUNDING SUPPORT

  1. American Heart Association (AHA)
  2. The NIH National Heart, Lung, and Blood Institute (NHLBI)
  3. West Virginia University Startup

 

MAJOR MODELS AND TECHNIQUES EMPLOYED

  • Left anterior descending artery (LAD) ligation and reperfusion (Ischemia-Reperfusion-IR injury) in vivo in mice to mimic Myocardial Infarction (MI)
  • Genetically modified- cardiac-specific knockout and overexpression mouse models
  • Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)
  • Adeno viral delivery of target genes to the heart
  • Neonatal Rat ventricular cardiomyocytes isolation and culture
  • Echocardiography to assess mouse cardiac function
  • Mitochondrial function analysis by Seahorse Extraflux analyzer
  • Multi-omics (transcriptomics, proteomics, and metabolomics) approaches