Khalimonchuk Lab

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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
402-472-8060

 

 

Research Overview:

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 programmed 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 for finding ways to combat these currently incurable diseases. Our research utilizes yeast, roundworm and mammalian cell models to address following fundamental questions:

Role of protein quality control in mitochondrial homeostasis and stress responses
Mitochondrial respiration is inherently linked to the 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 system (MPQC) represented by 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 proteasesand molecular chaperones, important functions of which remain obscure. We seek to elucidate the individual roles of various MPQC factors in the preservation of mitochondrial function and determine how impaired protein processing or turnover leads to a disease.

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 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, 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 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 handful of polypeptides originates 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, like cytochrome c oxidase, consist of proteins of the dual origin and harbor highly reactive prosthetic groups. To ensure normal mitochondrial function, a large number of dedicated chaperones and assembly factors assist and regulate biogenesis and maintenance of such complexes. We seek to understand how multi-protein complexes within the IM are formed and maintained, and how their erroneous biogenesis due to mutations in assembly factors drives clinical manifestations.

Oleh "Chuck" Khalimonchuk, Ph.D.

PhD, Dresden University of Technology/ Max Planck Insitute for Cell Biology & Genetics, Germany

Postdoctoral, University of Utah School of Medicine

Susan J. Rosowski Professor of Biochemistry

Oleh Khalimonchuk, Ph.D.

Research Interest:

I am interested in fundamental understanding of processes that underlie vital mitochondrial functions, and their contribution to complex maladies in humans. 

Email Oleh

Iryna Bohovych, Ph.D.

PhD, University of Aberdeen, Scotland, UK

Senior Research Associate

Iryna Bohovych, Ph.D.
Research Interest
:

I am interested in functional crosstalk between proteases- and ubiquitin/proteasome-mediated mitochondrial quality control in yeast and human cells.

Email Iryna

Nataliya Zahayko

MS, Lviv National University, Ukraine

Research Technician

Nataliya Zahayko

Research Interest:
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.

Email Nataliya

Edward Germany

BS, Texas A&M University at Galveston

Graduate Student

Edward Germany                                        
Research Interest:

I am interested in delineating the cellular functions of a novel mitochondrial AAA+ protein to better understand its role in neuronal health.

Email Ed

Jonathan Dietz

BS, Purdue University

Graduate Student

Jonathan Dietz

Research Interest:

I am interested in understanding the mecahnisms of mitochondrial heme transport and associated pathological states.

Email Jon

Martonio Ponte Viana

BS, Federal University of Ceara, Brazil

Graduate Student

Martonio Ponte Viana

Research Interest:

My research focus is to develop state-of-the-science genetic tools that will permit us to better understand how failing mitochodnrial fidelity contributes to aging and the development and progression of neurodegenerative diseases.

Email Martonio

Kimberly Stanke

BS, Michigan Technological University

Graduate Student (co-advised with Dr. Sri Kidambi, UNL Chemical & Biomolecular Engineering)

Kimberly Stanke

Research Interest:

I am interested in delineating molecular basis of neuro-glial communication to elucidate the role of astrocytes in disease-associated brain pathologies.

Email Kim

Timothy Hackett

BS, Iowa State University

Graduate Student (co-advised with Dr. Sri Kidambi, UNL Chemical & Biomolecular Engineering)

Timothy Hackett

Research Interest:

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.

Email Tim

PubMed Link

Complete list of our published work can be found at:

https://scholar.google.com/citations?user=k2OzIN0AAAAJ&hl=en&oi=ao

http://www.ncbi.nlm.nih.gov/myncbi/oleh.khalimonchuk.1/bibliography/public/

Selected Recent Publications:

1.      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 Sci131, pii: jcs219956.

2.      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.

3.      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.

4.      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.

5.      Swenson, S., Cannon, A., Harris, N.J., Taylor, N.G., Fox, J.L., Khalimonchuk, O. (2016) Analysis of oligomerization properties of heme a synthase provides insights into its function in eukaryotes. J. Biol. Chem. 291, 10411-10425.

6.      Navarro-Yepes, J., Annandurai, A., Bradley, E., Bohovych, I., Yarabe, B., de Jong, A., Ovaa, H., Khalimonchuk, O., Quintanilla-Vega, B., Franco, R. (2016) Inhibition of protein ubiquitination by paraquat and 1-methyl-4-phenylpyridinium impairs ubiquitin-dependent degradation pathways. Mol. Neurobiol. 53, 5229-5251.

7.    Bohovych, I., Fernandez, M.R., Rahn, J.J., Stakley, K.D., Bestman, J.E., Anandhan, A., Franco, R., Claypool, S.M., Lewis, R.E., Chan, S.S.L., Khalimonchuk, O. (2015) Metalloprotease OMA1 fine-tunes mitochondrial bioenergetic function and respiratory supercomplex stability. Sci. Rep. 5, 13989.

8.    Wilson, C., Natarajan, V., Hayward, S., Khalimonchuk, O., Kidambi, S. (2015) Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles. Nanoscale 7, 18477-18488.

9.    Anandhan, A., Rodriguez-Rocha, H., Zavala-Flores, L., Bohovych, I., Rochet, J.C., Lee, J., Khalimonchuk, O. Franco, R. (2015) Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways. Neurobiol. Dis. 81, 76-92.

10.    Bohovych, I., Donaldson, G., Christianson, S., Zahayko, N., Khalimonchuk, O. (2014) Stress-triggered activation of the metalloprotease Oma1 involves its C-terminal region and is important for mitochondrial stress protection in yeast. J. Biol. Chem. 289, 13259-13272.

Past Postdoctoral Fellows 

Kacoli Sen, PhD, Indian Institute of Technology
Present position: Postdoctoral Associate, University of Florida

Roman Levytskyy, PhD, UCSD
Present position: Staff Scientist, City of Hope National Medical Center

Past Graduate Students
Edward Germany, PhD '19

Present position: Postdoctoral Fellow, University of Miyazaki, Japan

Samantha Swenson, PhD '17 

Present position: Postdoctoral Fellow, University of Nebraska Medical Center

Christina Davis Wilson, PhD '16
(co-advised with Dr. Sri Kidambi, Chemical & Biomolecular Engineering)

Present position: Postdoctoral Fellow, Doane University

Past Undergraduate Students
Colton Roessner, BS '17

MD student, University of Nebraska Medical Center

Danelle Topil, BA '17

Intern, Catholic Teacher Corps Program at Creighton University 

Sara Christianson, BS '15

DO, Resident Physician, CoxHealth Medical System

Garrett Donaldson, BS '15

MD, Family Medicine Resident, Gundersen Health System

Andrew Cannon, BS '13

MD/PhD student, University of Nebraska Medical Center