The research goals of my laboratory involve the development of new tools and protocols in order to protect and maintain a healthy mitochondrial population. Mitochondrial dysfunction is central to the development and progression of many human diseases including neurodegeneration, cardiomyopathy, cancer, diabetes, and age-associated disorders. Our studies aim to contribute new and important information about how mitochondria sense and respond to various conditions of extracellular and intracellular stress. In addition, we expect to identify novel targets for the development of new and effective drugs for the multitude of human diseases where mitochondria dysfunction is known to be involved.
Our research efforts are focused on novel and significant mitochondrial dynamic states that operate under normal conditions but are also indispensable for cell survival during environmental stress or injury. One of the focal points of our current research is the mitochondrial pathway that has as central player the Omi/HtrA2 protease that was originally isolated and characterized in my laboratory. We have established the crucial role of this pathway in protein quality control, stress signaling, mitophagy, and cell death. Animals that lack a functional Omi/HtrA2 protease invariably develop a plethora of defects, in addition to severe cardiomyopathy, neurodegeneration, and premature aging.
Our work aims to understand the regulation of the Omi/HtrA2 pathway both under normal or stress conditions, and characterize all proteins involved. In addition, we are investigating how inactivation of different steps in this pathway can lead to mitochondrial dysfunction and the development and/or progression of human disease.
- Cilenti L, Mahar R, Di Gregorio J, Ambivero CT, Merritt EM, Zervos AS. Regulation of metabolism by mitochondrial MUL1 E3 ubiquitin ligase. Front. Cell Dev. Biol. 2022; 10:904728. doi.org/10.3389/fcell.2022.904728
- Di Gregorio J, Cilenti L, Ambivero CT, Andl T, Liao R, Zervos AS. UBXN7 cofactor of CRL3KEAP1 and CRL2VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1a BBA – Molecular Cell Research. 2021; 10.1016/j.bbamcr.2021.118963
- Cilenti L, Di Gregorio J, Ambivero CT, Andl T, Liao R, Zervos AS. Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein. Sci Rep. 10, 1609 (2020). https://doi.org/10.1038/s41598-020-58484-8
- Ismail OZ, Sriranganathan S, Zhang X, Bonventre JV, Zervos AS, Gunaratnam L. Tctex-1, a novel interaction partner of Kidney Injury Molecule-1, is required for efferocytosis. J Cell Physiol. 2018;233:6877–6895. https://doi.org/10.1002/jcp.26578
- Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2016; 2;12(1):1-222
- Ambivero CT, Cilenti L, Main S, and Zervos AS. Mulan E3 ubiquitin ligase interacts with multiple E2 conjugating enzymes and participates in mitophagy by recruiting GABARAP. Cell Signal. 2014; 26(12): 2921-2929.
- Cilenti L, Ambivero CT, Ward N, Alnemri ES, Germain D, and Zervos AS. Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochim Biophys Acta. 2014; 1843(7): 1295-307.
- Kang S, Louboutin JP, Datta P, Landel CP, Martinez D, Zervos AS, Strayer DS, Fernandes-Alnemri T, Alnemri ES. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ. 2013; 20(2): 259-269.
- Ambivero CT, Cilenti L, Zervos AS. ATF4 interacts with Abro1/KIAA0157 scaffold protein and participates in a cytoprotective pathway. Biochim Biophys Acta. 2012; 1823(12): 2149-2156.
- Balakrishnan M.P., Cilenti L., Ambivero C., Goto Y., Takata M., Turkson J., Li X.S., Zervos A.S. THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death. Biochem Biophys Res Commun. 2011; 7;404(1):195-200.
- Cilenti L., Balakrishnan M.P., Wang X-L., Ambivero C., Sterlicchi M., del Monte F., Ma X-L., and Zervos A.S. Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination. Journal of Molecular and Cellular Cardiology. 2011; 50(4):652-661
- Kim J, Kim DS, Park MJ, Cho HJ, Zervos AS, Bonventre JV, Park KM. Omi/HtrA2 protease is associated with tubular cell apoptosis and fibrosis induced by unilateral ureteral obstruction. Am J Physiol Renal Physiol. 2010; 298(6):F1332-1340.
- Balakrishnan MP, Cilenti L, Mashak Z, Popat P, Alnemri ES, Zervos AS. THAP5 is a human cardiac specific inhibitor of cell cycle that is cleaved by the pro-apoptotic Omi/HtrA2 protease during cell death. Am J Physiol Heart Circ Physiol. 2009;297(2):H643-653.
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