Oleh Khalimonchuk, PhD
N230 Beadle Center
University of Nebraska-Lincoln
Lincoln, NE 68588-0662
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 of 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 questions:
Role of the protein quality control in mitochondrial homeostasis and stress response
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 (MQC) 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. MQC comprises a number of highly conserved proteases, important functions of which remain obscure. We seek to elucidate the individual roles of various mitochondrial proteases in the preservation of mitochondrial function and determine how impaired protein processing or turnover leads to a disease.
Biogenesis and maintenance of the 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 assure 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 the clinical manifestations.