Anna-Liisa Nieminen, Ph.D.

Professor
Department: Drug Discovery & Biomedical Sciences
Programs: Cellular Injury, End Organ Disease

 

 

Research Interests:

Dr. Nieminen earned her PhD from the University of Kuopio, Finland in 1991. Over the course of her career as a faculty member at the University of North Carolina - Chapel Hill, Case Western Reserve University, and Medical University of South Carolina (MUSC), she published over 80 peer-reviewed publications, 30 book chapters, and co-edited 1 book.

Dr. Nieminen works on mechanisms of mitochondrial dysfunction, focused in particular on liver injury and hepatocytes. Her current research focuses on the mitochondrial iron uptake and release pathways and their role in hepatotoxicity. Biosynthesis of heme and Fe-S clusters essential for cellular function requires mitochondrial iron uptake. However, mitochondrial iron overload is damaging to organs like liver, heart, and brain. Iron in the presence of H2O2 promotes the Fenton reaction, which produces toxic hydroxyl radicals (•OH), ultimately resulting in cell death. Mitoferrin (Mfrn1/2) and the electrogenic mitochondrial calcium uniporter (MCU) in the mitochondrial inner membrane are the principal pathways for mitochondrial iron transport. Multiple methodologies (immuno-precipitation pull down, Duolink proximity assay, super-resolution imaging) provide evidence of overlapping localization of Mfrn2 and MCU in the mitochondrial inner membrane. In mitochondrial iron overload, high-capacity MCU may be the main driver for Fe2+ uptake, whereas Mfrn appears to be a lower-capacity transporter for Fe2+ uptake under physiological conditions. Acetaminophen (APAP) overdose causes hepatocellular injury from mitochondrial dysfunction. APAP causes iron release from lysosomes, which subsequently translocates into mitochondria via MCU to promote intramitochondrial formation of reactive oxygen species, onset of the mitochondrial permeability transition (MPT), and ultimately hepatotoxicity. Knockout of MCU protects against APAP-induced mitochondrial depolarization and cell death in vivo and in vitro. Conversely, knockout of mitoferrin enhances APAP hepatotoxicity, suggesting that mitoferrin becomes a release pathway after APAP-induced mitochondrial iron overload. Furthermore, recent studies in plasma membrane permeabilized hepatocytes suggest that mitoferrin is a Na+-independent electrogenic exchanger catalyzing Fe2+/3H+ exchange. These findings suggest that mitochondrial iron uptake is a double-edged sword beneficial for normal cellular functioning but detrimental in promoting oxidative stress and cell death when in excess.

Dr. Nieminen applies new techniques of quantitative laser scanning confocal and super-resolution microscopy for physiological and pathological analysis of mitochondria and other organelles, such as lysosomes, in living cells and the intact tissues of living animals. The DDRCC will provide valuable resources to execute these experiments. Dr. Nieminen will make extensive use of confocal and super-resolution imaging through the Advanced Imaging Core. The Proteomics Core will also be utilized to assess protein-protein interactions between various proteins related to mitochondrial iron uptake. She will also make great use of the new Bioanalytical and Biospecimen core, which will support data analysis. Finally, Dr. Nieminen is an active participant in Enrichment activities and is a highly active and effective collaborator.

Publications:

PubMed Collection