The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution
Open accessAbstract
Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments for incorporation into a variety of hemoproteins. The heme biosynthesis enzymes have been proposed to exist in a metabolon, a protein complex consisting of interacting enzymes in a metabolic pathway. Metabolons enhance the function of enzymatic pathways by creating favorable microenvironments for pathway enzymes and intermediates, facilitating substrate transport, and providing a scaffold for interactions with other pathways, signaling molecules, or organelles. Herein we detail growing evidence for a mitochondrial heme metabolon and discuss its implications for the study of heme biosynthesis and cellular heme homeostasis.
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Mitochondria regulate key cellular processes including energy production, apoptosis, calcium regulation and thermogenesis.
“The mitochondrion regulates various biological pathways (for example, cellular energy production, apoptosis, calcium regulation and thermogenesis)”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [6]
The section ‘The (Mitochondrial) Heme Synthesis Metabolon’ (page unavailable) discusses mitochondrial carbon flux and its interplay with the TCA cycle, while the References (page unavailable) include studies linking mitochondrial membrane changes to apoptosis. These provide limited support for metabolic and apoptotic roles, but the paper does not state the broader claim about energy production or address calcium regulation or thermogenesis. (LLM, conf=0.72)
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Yang, S., Gruber, A., Jiroutová, K., Richtová, J., Vancová, M., Tesařová, M., Masařová, P., Dorrell, R. G., & Obornı́k, M. (2025) · Frontiers in Plant Science · doi:10.3389/fpls.2025.1537037 · Cited by 1 · see citing works
Martinez-Guzman, O., Willoughby, M. M., Saini, A. G., Dietz, J. V., Bohovych, I., Medlock, A. E., Khalimonchuk, O., & Reddi, A. R. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/734780 · Cited by 1 · see citing works
Self-citationCarbon Monoxide and Mitochondria
Piantadosi, C. A. (2022) · Wiley eBooks · doi:10.1002/9781119783435.ch6 · Cited by 1 · see citing works
Cofactors and Coenzymes | Porphyrin Metabolism in Eukaryotes
Piel, R. B., Dailey, H. A., & Medlock, A. E. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00074-8
Self-citationAI-guided cryo-EM probes a thermophilic cell-free system with succinyl-coA manufacturing capabilityPreprint
Skalidis, I., Kyrilis, F. L., Tüting, C., Hamdi, F., Träger, T. K., Belapure, J., Hause, G., Fratini, M., O’Reilly, F. J., Heilmann, I., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.08.511438
Kaur, K. K., Allahbadia, G. N. K., & Singh, M. (2024) · British journal of healthcare and medical research · doi:10.14738/bjhmr.115.17586
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Poonaki, E., Badlah, S., Kahlert, U. D., Meuth, S. G., Stummer, W., & Gorji, A. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111480
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Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2
Ward, A. S., Kamath, V. G., Hsiung, C., Lizenby, Z. J., Gillish, A. G., Kohtz, D. S., & McKee, E. E. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110733
Light-Induced Transcription in Zebrafish Targets Mitochondrial Function and Heme Metabolism
Boiti, A., Weber, H. T., Hong, Y., Siauciunaite, R., Gornik, S. G., Foulkes, N. S., & Vallone, D. (2025) · Antioxidants · doi:10.3390/antiox14101151
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Racho, J., Stobbe, D., Jirschitzka, J., Croon, M., Petrungaro, C., Ali, M., Wernet, D., Habich, M., Gawellek, N. S., Strippel, J., et al. (2026) · Science Advances · doi:10.1126/sciadv.aed2430
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Dailey, H. A. (2026) · Chemical Reviews · doi:10.1021/acs.chemrev.6c00368
Self-citation
- Authors
- Piel, R. B., Dailey, H. A., & Medlock, A. E.
- Affiliations
- University of Georgia (US)
- Corresponding author
- Medlock, Amy E.
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 128
- Issue
- 3
- Pages
- 198-203
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC6640082
- OpenAlex
- W2908673125
- Cited by
- 59
- References
- 53
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 5 · 2023: 13 · 2022: 11 · 2021: 9 · 2020: 3 · 2019: 1
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK096501, DK111653, U54 DK110858)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- heme biosynthesis, heme homeostasis, heme proteins, protein complex formation, enzyme microenvironment, substrate transport, heme toxicity
- MeSH terms
- Animals, Heme, Homeostasis, Humans, Mitochondria, Mice, Metabolic Networks and Pathways, Metabolome
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