Venkatesh Sundararajan

Associate Professor

Organization:

West Virginia University School of Medicine

Department:

Physiology, Pharmacology & Toxicology

Classification:

Faculty

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

1. Muthu S, Tran Z; Thilagavathi J, Bolarum T, Azzam E, Suzuki CK, Venkatesh S. Aging triggers mitochondrial, endoplasmic reticulum and metabolic stress responses in the heart. J Cardiovasc Aging . 2025 Jan;5(1):4.
    
2. Rai NK, Venugopal H, Rajesh R, Ancha P, Venkatesh S. Mitochondrial complex-1 as a therapeutic target for cardiac diseases. Mol Cell Biochem. 2024. Mol Cell Biochem. 2024 Dec;479(12):3493.
    
3. Tran Z, Muthu S, Karelina K, Dwyer KO, Pal S, Sundararajan V. Cardiac Mitochondrial Dysfunction Induces Region-Specific Mitochondrial Stress Response In The Brain To Adapt Neuronal Changes. Circulation Research. 2024. 135 (Suppl_1), ATu044-ATu044.
    
4. Muthu S, Tran Z, Dwyer KO, Guppi S, Pal S, Velayutham V, Meadows E, Hollander J, Sundararajan V. The Mitochondrial LonP1 Is Indispensable For Cardiac Maturation And Function. Circulation Research. 2024. 135 (Suppl_1), ATu118-ATu118
    
5. Pal S, Eminhizer N, Dwyer KO, Muthu S, Tran Z, Prabhu S, Velayutham V, Chantler P, Sundararajan V.  Induction of Mitochondrial and Endoplasmic Reticulum Stress in Early Response to High-Fat Diet-Induced Hyperglycemia in Mouse Hearts. Circulation Research. 2024. 135 (Suppl_1), ATu122-ATu122
    
6. Lail N, Pandey AK, Venkatesh S, Noland RD, Swanson G, Pain D, Branson HM, Suzuki CK, Yoon G. Child Neurology: Progressive Cerebellar Atrophy and Retinal Dystrophy - Clues to an Ultra-Rare ACO2-Related Neurometabolic Diagnosis. Neurology. 2023 Oct 10;101(15):e1567–e1571.
    
7.  Sankar S, Jayabalan M, Venkatesh S, Ibrahim M.  Effect of hyperglycemia on tbx5a and nppa gene expression and its correlation to structural and functional changes in developing zebrafish heart. Cell Biol Int. 2022 Sep 7. doi: 10.1002/cbin.11901.
    
8. Muthu S Sukumaran V and Venkatesh S. Editorial: Understanding Molecular Mechanisms in Diabetic Cardiomyopathy (DCM) Front. Cardiovasc. Med. 2022;9:965650.
    
9. 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.
    
10. 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.
     
11. 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.
     
12. S 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.
     
13. 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.
     
14. 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)
     
15. 15.  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).
     
16. 16.  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).
     
17. 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).
     
18. 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.
     
19. 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)
     
20. 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).
     
21. 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.
     
22. 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.
     
23. Venkatesh S, & Suzuki CK (2017). HSP60 Takes a Hit: Inhibition of Mitochondrial Protein Folding. Cell Chem Biol 24: 543-545.
     
24. 24.  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.
     
25. 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.
     
26. 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.
     
27. 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)
     
28. Thilagavathi J, Venkatesh S, & Dada R (2013). Telomere length in reproduction. Andrologia 45: 289-304.
     
29. 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.
     
30. 30.  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.
     
31. 31.  Thilagavathi J, Venkatesh S, Kumar R, & Dada R (2012). Segregation of sperm subpopulations in normozoospermic infertile men. Syst Biol Reprod Med 58: 313-318.
     
32. 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.
     
33. 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.
     
34. 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.
35. 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.
     
36. 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.
     
37. 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.
     
38. 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.
     
39. 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.
     
40. 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.
     
41. Venkatesh S, & Dada R (2011). An evolutionary insight into mutation of ATPase6 gene in primary ovarian insufficiency. Arch Gynecol Obstet 284: 251-252.
     
42. 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.
     
43. 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.
     
44. 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.
     
45. 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.
46. 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.
     
47. 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.
     
48. 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.
     
49. 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.
     
50. 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.
     
51. 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.
     
52. 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.
     
53. 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.

Graduate Program Affiliations: Cellular and Integrative Physiology, Pharmaceutical and Pharmacological Sciences

MAJOR PROJECTS UNDERWAY

• In one of our major research projects, we are investigating the role of mitochondrial LonP1 in cardiac function and protection. Specifically, we are focused on myocardial ischemia-reperfusion (IR) injury, a major clinical challenge in the treatment of myocardial infarction (MI)—the leading cause of death worldwide. Mitochondrial reactive oxygen species (mtROS), primarily generated by Complex I of the electron transport chain (ETC), are key mediators of IR injury. Excess mtROS produced during the early reperfusion phase initiates a vicious cycle of free radical generation that promotes cardiomyocyte death. Understanding the early molecular events during reperfusion is therefore critical for identifying novel therapeutic targets to limit cardiac injury. Our published studies have demonstrated that LonP1, a major mitochondrial stress response protease, plays a protective role by mitigating oxidative stress-induced damage during early IR. Based on this, we propose that LonP1 represents a promising therapeutic target for attenuating reperfusion injury. Our long-term goal is to leverage mitochondrial protein quality control (MPQC) pathways regulated by LonP1 to develop therapeutic strategies—such as targeted delivery of LonP1 to the heart or activating LonP1 using small molecules—to prevent IR injury and post-MI heart failure. To gain deeper mechanistic insights, we are also using cardiomyocyte-specific LonP1 conditional knockout mouse models to determine whether LonP1 is essential for maintaining cardiac function under basal and stress conditions. To address the human clinical relevance, we complement our in vivo studies using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, enabling us to assess the impact of LonP1 manipulation in a translationally relevant human cell model.
   
•  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. However, its action on non-replicating cardiomyocytes, leading to cardiotoxicity, is largely unknown. This gap in knowledge limits the identification of therapeutic strategies to treat DOX-induced cardiomyopathy. In this project, we hypothesize that DOX accumulates within mitochondria, binds to and releases mitochondrial DNA (mtDNA), and suppresses mitochondrial biogenesis, thereby inducing progressive mitochondrial and cardiac dysfunction. Supporting this hypothesis, our integrated studies using patient samples, human cardiomyocyte cell lines, and mouse models demonstrate that DOX dose-dependently promotes mtDNA release. We are further investigating whether LonP1 plays a protective role against DOX-mediated mitochondrial damage and cardiotoxicity. By elucidating the precise mechanisms of DOX-induced mitochondrial dysfunction, our goal is to develop novel, targeted, and clinically relevant strategies to prevent or mitigate heart failure in cancer patients receiving anthracycline therapy.
   
• In another major project, we are investigating the role of mitochondrial protein quality control in diabetic cardiomyopathy, with a particular focus on the mitochondrial matrix protease LonP1. The healthy adult heart relies predominantly on fatty acid oxidation (FAO) for ATP production, with the flexibility to switch to glucose oxidation as needed. In type 2 diabetes, chronic hyperglycemia and insulin resistance limit glucose utilization, forcing the heart to rely almost exclusively on FAO. This metabolic inflexibility overburdens the mitochondria, leading to oxidative stress, reduced efficiency, and progressive dysfunction. We hypothesize that impaired LonP1 function exacerbates this mitochondrial stress by disrupting proteostasis, leading to the accumulation of damaged proteins, altered metabolic substrate handling, and diastolic dysfunction. Using cardiac-specific LonP1 transgenic and knockout mouse models subjected to high-fat diet and low-dose streptozotocin-induced diabetes, we are examining the impact of LonP1 on mitochondrial integrity, substrate utilization, and cardiac performance. Our preliminary data show that mice with adult-onset cardiac-specific LonP1 deletion maintain normal baseline cardiac function but, when fed a high-fat diet, fail to gain weight and exhibit improved glucose tolerance compared to controls—suggesting an unexpected metabolic adaptation. Ultimately, our goal is to define the mechanistic role of LonP1 in diabetic cardiomyopathy and determine whether targeting LonP1-mediated protein quality control can be leveraged as a therapeutic strategy to preserve or restore mitochondrial and cardiac function in diabetes.

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

• 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
• Echocardiography to assess mouse cardiac function
• Mitochondrial function by complex activities and oxygen consumption assays
• Multi-omics (transcriptomics, proteomics, and metabolomics) approaches

MENTORING PHILOSOPHY

My mentoring philosophy is centered on creating a supportive and intellectually stimulating environment that encourages independence, critical thinking, and collaboration. I tailor my mentoring style to each trainee’s goals and strengths, while maintaining high expectations for scientific rigor and integrity. I provide structured guidance early on and gradually promote autonomy as confidence and skills develop. Regular one-on-one meetings, open communication, and a team-based lab culture are key components of my approach. Ultimately, my goal is to empower mentees to become thoughtful, resilient, and ethical scientists who can thrive in diverse research and career settings.