Current Activities
The Lindahl lab is interested in the cellular biochemistry of iron and copper. Transition metals have exceptional redox and catalytic properties that render them indispensable for life. However, they also help generate reactive oxygen species which damage cells and contribute to aging and disease. Thus, cells must tightly regulate metal-ion trafficking. There are huge gaps in understanding the biochemistry of metal ion trafficking and regulation in cells, and we are developing innovative and powerful approaches to fill them. The “Grand Central Station” of Fe trafficking is the cytosolic Labile Fe Pool. The iron in this pool consists of non-proteinaceous, low-molecular-mass coordination complexes with O/N/S donor ligands. Their existence has been recognized for a half-century but their molecular and cellular properties remain unestablished. We are also interested in mitochondria, the primary site of iron-sulfur cluster assembly, the only site of heme biosynthesis, and the location of heme-and-copper-containing cytochrome c oxidase. Dysregulation of iron trafficking into this organelle plays a critical role in Friedreich’s Ataxia, a disease in which iron-sulfur cluster assembly is inhibited due to lack of frataxin in humans.
We are also interested in how cytosolic copper is transported into mitochondria, the molecular details of cytosolic copper homeostasis, and the characterization of the labile Cu pools in cells. Another focus is non-transferrin-bound iron (NTBI), a mysterious form of iron found in the blood of individuals suffering from hereditary hemochromatosis. We are currently investigating the possibility that NTBI is a nonproteinaceous FeIII aggregate of nanoparticles.
We study labile metal pools using a novel liquid chromatography system housed in a refrigerated glove box and interfaced to an inductively coupled plasma mass spectrometer. We have 4 Mössbauer spectrometers which are used to characterize the iron content of cells and organelles. Mathematically inclined lab members develop ordinary-differential-equations-based models to help quantify the kinetics and mechanism of Fe trafficking in eukaryotic cells. Thus, the lab is highly diverse in approach, involving cell biology, biochemistry, bioinorganic, bioanalytical, and biophysical chemistry, and well as mathematical modeling. This diversity allows us to probe deeply into issues of cellular metal-ion biochemistry and the connection to human disease. Students with all sorts of diverse backgrounds and research interests are welcome to join us.
Educational Background
B. A., 1979, North Park College
Ph. D., 1985, Massachusetts Institute of Technology
NIH Postdoctoral Fellow, 1985-87, University of Minnesota
Selected Publications
- Moore M.J., Wofford, J.D., Dancis, A., and Lindahl P.A. (2018) “Recovery of mrs3mrs4 Saccharomyces cerevisiae cells under iron-sufficient conditions and the role of Fe580” Biochemistry 57, 672-683.
- Lindahl P.A. (2019) A comprehensive mechanistic model of iron metabolism in Saccharomyces cerevisiae. Metallomics, 11, 1779-1799.
- Pandey A, Pain P, Dziuba N, Pandey A.K., Dancis A, Lindahl P.A. and Pain D. (2018) “Mitochondria Export Sulfur Species Required for Cytosolic tRNA Thiolation” Cell Chemical Biology 25, 738-748.
- Dziuba N., Hardy J., and Lindahl P.A. (2018) “Low-molecular-mass iron in healthy blood plasma is not predominately ferric citrate” Metallomics, 10, 802-817.
- Wofford J.D., Bolaji N., Dziuba N, Outten, F.W., Lindahl P.A. (2019) “Evidence that a respiratory shield in E. coli protects a low molecular mass FeII pool from O2-dependent oxidation” J. Biol. Chem., 294, 50-62.
- Wofford J.D. and Lindahl P.A. (2019) “A mathematical model of iron import and trafficking in wild-type and Mrs3/4ΔΔ yeast cells” BMC Systems Biology 13: Article number 23 DOI: 10.1186/s12918-019-0702-2
- Nguyen T.Q., Dziuba N., and Lindahl P.A. “Isolated Saccharomyces cerevisiae Vacuoles contain Low-Molecular-Mass Transition-Metal Polyphosphate Complexes” (2019) Metallomics, DOI: 10.1039/c9mt00104b.
- Soma S., Morgada M.N., Naik M.T., Boulet A., Roesler A.A., Dziuba N., Ghosh A., Yu Q.H., Lindahl P.A., Ames J.B., Leary S.C, Vila A.J, and Gohil V.M. (2019) “COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase: Cell Reports 29, 4114-4126. DOI: 10.1016/j.celrep.2019.11.054
- Dziuba N., Hardy J., and Lindahl P.A. (2019) “Low-molecular-mass iron complexes in blood plasma of iron-deficient pigs do not originate directly from nutrient iron” Metallomics, 11. DOI: 10.1039/c9mt00152b
- Drake H.F., Day G.S., Vali S.W., Xiao Z., Banerjee S., Li J.L., Joseph E.A., Kuszynski J.E., Perry Z.T., Kirchon A., Ozdemir O.K., Lindahl P.A., and Zhou H.C. (2019) “The thermally induced decarboxylation mechanism of a mixed-oxidation state carboxylate-based iron metal-organic framework” Chemical Communications. 55, 12769-12772.
- Lindahl P.A. “Acetyl-coenzyme A synthase: a beautiful metalloenzyme” in “Bioorganometallic Chemistry” (Ulf-Peter Apfel and Wolfgang Weigand, Editors). De Gruyter, Berlin, Germany. 2020, Chapter 7, pp 279-312. https://doi.org/10.1515/9783110496574-007
- Nguyen T.Q, Kim J.E., Brawley H.N., and Lindahl P.A. (2020) “Chromatographic detection of low-molecular-mass metal complexes in the cytosol of Saccharomyces cerevisiae” Metallomics, 12, 1094-1105.
- Khan D., Lee D.J., Gulten G., Aggarwal A., Wofford J.D., Krieger I., Tripathi A., Patrick J.W., Eckert D.M., Laganowsky A.A., Sacchettini J., Lindahl P.A., Bankaitis V.A., (2020) “A Sec14-like phosphatidylinositol transfer protein paralog defines a novel class of heme-binding proteins” ELIFE 9, Article Number: e57081
- Kim J.E., Vali S.W., Nguyen T.Q., Dancis A., and Lindahl P.A. (2021) “Mössbauer and LC-ICP-MS investigation of iron trafficking between vacuoles and mitochondria in Vma2 Saccharomyces cerevisiae” Journal of Biological Chemistry Article number 100141, https://doi.org/10.1074/jbc.RA120.015907. Pp. 1-14.
- Brawley H.N. and Lindahl P.A. (2021) “Low‑molecular‑mass labile metal pools in Escherichia coli: advances using chromatography and mass spectrometry” J. of Biological Inorganic Chemistry 26, 479–494.
- Vali S.W., Haja D.K., Brand R.A., Adams M.W.W., and Lindahl P.A. (2021) “The Pyrococcus furiosus ironome is dominated by [Fe4S4]2+ clusters or thioferrate-like iron depending on the availability of elemental sulfur” Journal of Biological Chemistry 296, article 100710, pp. 1-15.
- Brawley, H.N., Lindahl P.A. (2021) Direct detection of the labile nickel pool in Escherichia coli: new perspectives on labile metal pools. Journal of the American Chemical Society. 143, 18571-18580.
- Hyun, S., Reid, K. A., Vali, S.W., Lindahl P.A., & Powers, D. C. Cis-divacant octahedral Fe(II) in a dimensionally reduced family of 2-(Pyridin-2-yl)pyrrolide complexes. Inorg. Chem. 2021, 60, 15617-15626.
- Fernandez, S., Wofford, J.D., Shepherd, R.E., Vali, S.W., Dancis, A., and Lindahl P.A. (2022) Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: studies using Mössbauer spectroscopy and mathematical modeling. Journal of Biological Chemistry 298, 101921, 1-16.
- Kim, J.E and Lindahl P.A. (2022) CUP1 metallothionein from healthy Saccharomyces cerevisiae colocalizes to the cytosol and mitochondrial intermembrane space. Biochemistry, in press.
- Vali, S.W. and Lindahl P.A. (2022) Low-temperature Mössbauer spectroscopy of organs from 57Fe-enriched HFE(-/-) hemochromatosis mice: iron-dependent threshold for generating hemosiderin. Journal of Biological Inorganic Chemistry, in press.
- Vali, S.W. and Lindahl P.A. (2022) Might non-transferrin-bound iron in blood plasma and sera be a non-proteinaceous high-molecular-mass FeIII aggregate? Journal of Biological Chemistry, in press.
- Lindahl P.A. and Vali, S.W. (2022) Mössbauer-based molecular-level decomposition of the Saccharomyces cerevisiae ironome, and preliminary characterization of isolated nuclei. Metallomics, 14, in press.
- Brawley H.N., Kreinbrink, A., Hierholzer J., Vali, S.W., and Lindahl P.A. (2022) The Labile Iron Pool of Isolated Escherichia coli Cytosol likely Includes Fe-ATP and Fe-citrate but not Fe-Glutathione or Aqueous Fe. Journal of the American Chemical Society, in press.
