Kristian Want

Postdoctoral Researcher, Brandeis University

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Lab Affiliations

Current Postdoctoral Research

Fe-S clusters are among the most ancient of cofactors, required for the sustained life of essentially all living cells on Earth today. In humans, the main housekeeping assembly of Fe-S clusters takes place in the mitochondria, earning the organelle more credit than just being the “powerhouse of the cell.” Unfortunately, a vast array of diseases exist due to mutations in any of the many genes involved in mitochondrial Fe-S assembly such as Friedreich’s ataxia (FRDA). Thus, my current research aims to extend our understanding of mitochondrial Fe-S metabolism while discovering and exploring new therapeutic avenues for the treatment of related diseases.

I work within the Meisel and Pandelia labs at Brandeis University, which specialize in genetics and biochemistry, respectively. My research bridges their expertise with structural biology to study the intricate assembly pathways involved in [2Fe-2S] and [4Fe-4S] cluster synthesis, and to map how these clusters are exported from the mitochondria or transferred to relevant apo-proteins. Within this scope, I also explore how known human diseases disrupt these processes, with a particular focus in FRDA and MMDS. To achieve this, I use C. elegans as a tractable animal model, applying forward genetic screens to discover suppressor mutations able to rescue mitochondrial dysfunction. The mechanisms of these suppressor mutations are then characterized using a repertoire of in silico, in vitro, and in vivo techniques, laying a foundational platform for the treatment of these diseases. These discoveries are then applied to either guide virtual screening of small-molecule drug candidates or the rational design of recombinant proteins compatible with gene- and protein-replacement therapy. Therapeutic leads are assayed within in vitro reconstituted Fe-S systems for high-throughput assay and optimization, which guides in vivo physiologically-relevant activity assays.

Taken together, this research aims to significantly enhance our understanding of Fe-S metabolism, and provide new therapeutic strategies for those within unmet clinical needs.

Ph.D. Research

My doctoral research was performed under the mentorship of Dr. Benoit D’Autreaux at the Institute for Integrative Biology of the Cell (I2BC), with my doctorate in Biochemistry and Structural Biology awarded by the Université Paris-Saclay.

This work focused on characterizing the interactions and activity of FXN and FDX2 during the assembly of [2Fe-2S] clusters using a combination of biochemical, biophysical, and genetic techniques. This work led to the discovery that ferredoxin-2 (FDX2) and frataxin (FXN) must be intricately balanced for optimal [2Fe-2S] cluster synthesis efficiency, and that FDX2 has an unexpected auto-inhibitory role of slow persulfide transfer during [2Fe-2S] synthesis. Bringing this work together, we showed that decreasing the concentration of FDX2 significantly extends lifespan in a Friedreich’s Ataxia (FRDA) model of D. melanogaster, thus opening a new therapeutic avenue for treatment of FRDA.

Before this work, the project was focused on the design of novel therapeutics including small molecules and short peptides to treat FRDA.

Structural details of the FDX2–NFS1–ISCU2 interface are presented in our Nature publication.

Master’s Research

My Master’s research was performed under the mentorship of Dr. Glyn Hemsworth at the University of Leeds, focused on mapping and characterizing the interaction between an AA10 LPMO with its proposed redox-active heme-containing partner protein. De novo protein-protein docking was performed using HADDOCK, giving models which were experimentally verified within the lab using chemical-crosslinking mass spectrometry. This was ultimately awarded the highest research project grade among the Master’s cohort.