Welcome to the Khalimonchuk Lab at the University of Nebraska
Work in our lab is focused on fundamental biological processes that involve mitochondria. To gain insights into vital aspects of mitochondrial biology and human disease and aging, we utilize several model systems and state-of-the-art genetics and biochemical approaches as well as various physiological and imaging techniques.
Department of Biochemistry
University of Nebraska
N230 Beadle Center
Lincoln, NE 68588-0664
Mitochondria are complex and highly dynamic organelles responsible for a number of vital functions including cellular energy conversion, a plethora of metabolic and biosynthetic pathways, maintenance of ion homeostasis and cell death. Perturbations to mitochondrial function and integrity lead to dysfunctions that manifest in a spectrum of early- to adult-onset neurological and cardiovascular disorders, certain types of cancer, Type II diabetes and neurodegeneration. Understanding the molecular bases of mitochondrial function/dysfunction is a key to finding ways to combat these currently incurable diseases. Our research utilizes yeast, roundworm and mammalian cell culture models to address the following fundamental questions.
Role of protein quality control in mitochondrial homeostasis and stress responses
Mitochondrial respiration is inherently linked to generation of reactive oxygen species (ROS). In addition, redox-active intermediates in the biogenesis of the electron transfer chain respiratory complexes can further facilitate ROS production. Accumulating or persisting ROS can damage mitochondrial proteins and/or DNA located in the vicinity to respiratory chain, thereby contributing to mitochondrial dysfunction. Mitochondrial protein quality control (MPQC) system composed of molecular chaperones and proteases is a key factor that helps cells to cope with homeostatic challenges such as oxidative damage and protein misfolding. MPQC comprises a number of highly conserved proteases and molecular chaperones, important functions of which remain obscure. We seek to elucidate the individual roles of various MPQC components in preservation of mitochondrial functions and plasticity, and determine how impaired protein processing or turnover leads to aging-related diseases.
Mitochondrial heme transport
Heme is an essential, but inherently reactive and cytotoxic cofactor and signaling molecule. In most eukaryotes heme biosynthesis is initiated and completed within the mitochondria. All mitochondrial heme species are generated from heme b (aka protoheme) produced by the enzyme ferrochelatase and must be mobilized and trafficked for further distribution in virtually every subcellular compartment via largely unknown mechanisms. Our studies are aimed at understanding the mechanisms that govern safe mobilization, modification, transport and distribution of heme within and out of the mitochondria. Unraveling the molecular details of heme trafficking and export in health and disease states may identify targetable molecules for treatment of highly prevalent human disorders associated with heme and iron dyshomeostasis.
Biogenesis and maintenance of protein complexes within the inner mitochondrial membrane
The vast majority of proteins comprising mitochondrial proteome is synthesized in the cytosol and imported into the organelle, while only a handful of polypeptides originate from the mitochondrial genome. The inner mitochondrial membrane (IM) is an ultimate destination for many of these proteins wherein they are organized into high molecular weight complexes. Some of these assemblies such as cytochrome c oxidase (aka Complex IV), encompass proteins of dual genomic origin and harbor highly reactive prosthetic groups. To ensure normal mitochondrial function, numerous dedicated chaperones and assembly factors assist and regulate biogenesis and maintenance of these protein machineries. We seek to understand how the IM-localized multiprotein ensembles are formed and maintained, and how their erroneous biogenesis due to mutations in assembly factors drives clinical manifestations.
Oleh "Chuck" Khalimonchuk, Ph.D.
PhD, TU Dresden / Max Planck Insitute for Cell Biology & Genetics, Germany
Postdoctoral, University of Utah School of Medicine
Susan J. Rosowski Professor of Biochemistry
I am interested in fundamental understanding of processes that underlie vital mitochondrial functions, and their contribution to complex maladies in humans.
Iryna Bohovych, Ph.D.
PhD, University of Aberdeen, Scotland, UK
Senior Research Associate
I am interested in functional crosstalk between proteases- and ubiquitin/proteasome-mediated mitochondrial quality control in yeast and human cells.
Gunjan Purohit, Ph.D.
PhD, New Delhi Institute of Genomics & Integrative Biology, India
Postdoctoral Research Associate
My research focus is to understand how failing mitochondrial fidelity contributes to aging and the development and progression of neurodegenerative diseases.
MS, Lviv National University, Ukraine
I am interested in developing genetic tools in the roundworm Caenorhabditis elegans model that will allow us to study how mitochondrial dysfuntion contributes to aging-related neuromuscular diseases in humans.
BS, Interamerican University, Puerto Rico
I am interested in delineating molecular basis of redox regulation of mitochodnrial quality control factors to elucidate their role in mitochondrial stress remodeling and relevant disease states.
BS and MS, Mawlana Bhashani Science & Technology University, Bangladesh
I am interested in delineating the role of a conserved metalloprotease in the mitochondrial protein homeostasis and its contribution to human neuromuscular disorders.
BS, Iowa State University
Graduate Student (co-advised with Dr. Sri Kidambi, UNL Chemical & Biomolecular Engineering)
I am interested in understanding the role of various tissue microenvironment factors such as stiffness in microglia molecular and metabolic reprogramming, leading to neurodegeneartive states during aging.
Complete list of our published work can be found at:
1. Nyvltova, E., Dietz, J.V., Seravalli, J., Khalimonchuk, O., Barrientos, A. (2022) Coordination of metal center biogenesis in human cytochrome c oxidase. Nature Commun. 13, 3615.
2. Dietz, J.V., Bohovych, I., Willoughby, M.M., Piel 3rd, R.B., Ross, T.A., Addis, H.G., Fox, J.L., Lanzilotta, W.N., Dailey, H.A., Wohlschlegel, J.A., Reddi, A.R., Medlock, A.E., Khalimonchuk, O. (2021) Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase. Redox Biol. 46, 102125.
3. Viana, M.P., Levytskyy, R.M., Anand, R., Reichert, A.S., Khalimonchuk, O. (2021) Protease OMA1 modulates mitochondrial bioenergetics and ultrastructure through dynamic association with MICOS complex iScience 24, 102119.
4. Martinez-Guzman, O., Willoughby M.M., Saini, A., Dietz, J.V., Bohovych, I., Medlock, A.E., Khalimonchuk, O., Reddi, A.R. (2020) Mitochondria-nuclear heme trafficking is regulated by GTPases that control mitochondrial dynamics and ER contact sites. J. Cell Sci. jcs.237917.
5. Daverey, A., Levytskyy, R.M., Swenson, S., Hayward, S.L., Stanke, K.M., Viana, M.P., Narasimhan, M., Khalimonchuk, O., Kidambi, S. (2019) Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells. Sci. Rep. 9, 14746.
6. Bohovych, I., Dietz, J.V., Swenson, S., Zahayko, N., Khalimonchuk, O. (2019) Redox regulation of the mitochondrial quality control protease Oma1. Antioxid. Redox Signal. 31, 429-443.
7. Germany, E.M., Zahayko, N., Huebsch, M., Fox, J.L., Prahlad, V., Khalimonchuk, O. (2018) The AAA-ATPase Afg1 preserves organellar fidelity and cellular healthspan by maintaining mitochondrial matrix proteostasis. J. Cell Sci. 131, pii: jcs219956.
8. Tsushima, K., Bugger, H., Wende, A.R., Soto, J., Jenson, G.A., Tor, A.R., McGlauflin, R., Kenny, H.C., Zhang, Y., Souvenir, R., Hu, X.X., Sloan, C.L., Pereira, R.O., Lira, V.A., Spitzer, K.W., Sharp, T.L., Shoghi, K.I., Sparagna, G.C., Rog-Zielinska, E.A., Kohl, P., Khalimonchuk, O., Schaffer, J.E., Abel, E.D. (2018) Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1 and OPA1 that promote mitochondrial fission. Circ. Res. 122, 58-73.
9. Taylor, N.G., Swenson, S., Harris, N.J., Germany, E.M., Fox, J.L., Khalimonchuk, O. (2017) The assembly factor Pet117 couples heme a synthase activity to cytochrome oxidase assembly. J. Biol. Chem. 292, 1815-1825.
10. Bohovych, I., Kastora, S., Christianson, S., Kim, H.J., Fangman, T., Zhou, Y.J., Barrientos, A., Brown, A.J., Khalimonchuk, O. (2016) Oma1 links mitochondrial protein quality control and TOR signaling to modulate physiological plasticity and cellular stress responses. Mol. Cell. Biol. 36, 2300-2312.
Past Postdoctoral Fellows
Kacoli Sen Banerjee, PhD, Indian Institute of Technology
Present position: Postdoctoral Associate, University of Florida
Roman Levytskyy, PhD, MBA, UCSD
Present position: Associate Director of Medical Affairs, Exelixis Inc.
Sang-Gyu Hwang, PhD, University of Ulsan College of Medicine
Present position: Research Scientist, University of Ulsan, South Korea
Ganapathi Kandasamy, PhD, University of Cologne
Present position: Postdoctroal Researcher, University of Miami
Past Graduate Students
Present position: Staff Scientist, Charles River Laboratories
Present position: Instructor in Statistics, University of Nebraska-Lincoln
Present position: Postdoctoral Fellow, Rutgers University
Present position: Senior Associate Scientist, Pfizer Inc.
Present position: Postdoctoral Fellow, University of Miyazaki, Japan
Present position: Instructor, University of Nebraska Medical Center
Present position: Postdoctoral Fellow, Doane University
Past Undergraduate Students
MD student, University of Nebraska Medical Center
DDS student, Creighton University School of Dentistry
Post-baccalaureate research associate at MIT, applying to MD/PhD programs
MD student, University of Nebraska Medical Center
MD, Anesthesiology Resident, Ohio State University Medical Center
Catholic Teacher Corps Program at Creighton University
DO, Resident Physician, CoxHealth Medical System
MD, Family Medicine Resident, Pella Regional Health Center
MD/PhD, Pathology Resident, Mayo Clinic