Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice

Possemato, R.; Molenaars, M.; Mir, H.; Schmidt, A. M.; Arivazhagan, L.; Rosselot, C.; Garcia-Ocana, A.; Park, C.; Zhan, D.; Alvarez, S.

doi:10.1101/2024.08.19.608291

bioRxiv · 10.1101/2024.08.19.608291

Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice

Possemato, R.·Molenaars, M.·Mir, H.·Schmidt, A. M.·Arivazhagan, L.·Rosselot, C.·Garcia-Ocana, A.·Park, C.·Zhan, D.·Alvarez, S.

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Abstract

Iron-sulfur clusters (ISCs) are cell-essential cofactors present in [~]60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/608291v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@863cbaorg.highwire.dtl.DTLVardef@fce90borg.highwire.dtl.DTLVardef@27df04org.highwire.dtl.DTLVardef@1a2a9bf_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Acute ISC inhibition leads to rapid loss of adiposity in mice - Multi-metabolic pathway disruption upon ISC deficiency blocks energy storage - Nfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in {beta}-cells - Energy distress caused by inhibition of ISC synthesis is attenuated in aged mice

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Possemato, R., Molenaars, M., Mir, H., Schmidt, A. M., Arivazhagan, L., Rosselot, C., Garcia-Ocana, A., Park, C., Zhan, D., Alvarez, S.. 2024-08-19. Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice. https://doi.org/10.1101/2024.08.19.608291

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