Abiotic origin of the citric acid cycle intermediates
Edited by Nigel J. Mason, University of Kent, Canterbury, United Kingdom; received January 24, 2025; accepted March 22, 2025 by Editorial Board Member Stephen J. Benkovic
Significance
The chemistry of cold molecular clouds is remarkably rich in complex organic molecules. By replicating the conditions of ice-coated nanoparticles in these cold regions of space, laboratory simulation experiments provide compelling evidence on the synthesis of the complete set of organics of the citric acid cycle in interstellar analog ices exposed to ionizing radiation. These findings illustrate a plausible starting point for developing molecular precursors to life in deep space in conjunction with the incorporation of these building blocks into solar systems, as evidenced by Ryugu and Murchison, potentially laying the groundwork for metabolic evolution and the Origins of Life.
Abstract
The molecular framework for protometabolism—chemical reactions in a prebiotic environment preceding modern metabolism—has remained unknown in evolutionary biology. Mono-, di-, and tricarboxylic acids that comprise contemporary metabolism, such as the Krebs cycle, are of particular prebiotic relevance and are theorized to predate life on Earth. Researchers have struggled to unravel the molecular origins of respiration, with theories pointing toward abiotic origins later co-opted by the earliest living organisms; however, the molecular network of these molecules has remained elusive. Recent detections of carboxylic acids linked to the Krebs cycle on the Ryugu asteroid and Murchison meteorite rekindled interest in their extraterrestrial origins. Replicating conditions analogous to the environment of dense molecular clouds in laboratory simulation experiments, our work provides compelling evidence on the abiotic synthesis of the complete suite of biorelevant molecules central to the Krebs cycle. The opportunity for these biomolecules forming in deep space could provide molecular origins of protometabolism on early Earth and also provide the molecular feedstock to worlds beyond our own.
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Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
Acknowledgments
The work at the University of Hawaii was funded by the US NSF Division of Astronomical Sciences, under grant AST-2403867. C.M. acknowledges funding from the Simone and Cino Del Duca Foundation—Institut de France as well as the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 804144). We would like to thank Yvonne Chan and Ethan Hill for advocacy and mentoring. We would also like to thank Kaelyn Pacpaco for her involvement in this work.
Author contributions
C.M. and R.I.K. designed research; M.M., J.B., A.M.T., and N.H. performed research; M.M., J.B., and D.M. analyzed data; and M.M. wrote the paper.
Competing interests
The authors declare no competing interest.
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Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
Submission history
Received: January 24, 2025
Accepted: March 22, 2025
Published online: April 21, 2025
Published in issue: April 29, 2025
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Acknowledgments
The work at the University of Hawaii was funded by the US NSF Division of Astronomical Sciences, under grant AST-2403867. C.M. acknowledges funding from the Simone and Cino Del Duca Foundation—Institut de France as well as the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 804144). We would like to thank Yvonne Chan and Ethan Hill for advocacy and mentoring. We would also like to thank Kaelyn Pacpaco for her involvement in this work.
Author contributions
C.M. and R.I.K. designed research; M.M., J.B., A.M.T., and N.H. performed research; M.M., J.B., and D.M. analyzed data; and M.M. wrote the paper.
Competing interests
The authors declare no competing interest.
Notes
This article is a PNAS Direct Submission. N.J.M. is a guest editor invited by the Editorial Board.
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Abiotic origin of the citric acid cycle intermediates, Proc. Natl. Acad. Sci. U.S.A.
122 (17) e2501839122,
https://doi.org/10.1073/pnas.2501839122
(2025).
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