Progesterone receptor membrane component 1 (PGRMC1) regulates Heme trafficking through mitochondria-ER junctions

Robert B Piel Iii¹, Chibuike D Obi¹, Martonio Ponte Viana², Mathilda M Willoughby³, Osiris Martinez-Guzman³, Aaliyah Wadley³, Yasaman Jami-Alahmadi⁴, James A Wohlschlegel⁴, Kevin G Hicks⁵, Jared Rutter⁶, J Alan Maschek⁷, J Leon Catrow⁸, James Cox⁹, Amit R Reddi¹⁰, Oleh Khalimonchuk¹¹, Amy E Medlock¹²

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
² Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA.
³ School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112, USA.
⁶ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁷ Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁸ Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁹ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
¹⁰ School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
¹¹ Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA; Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA.
¹² Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA; Department of Interdisciplinary Biomedical Sciences, University of Georgia School of Medicine, Athens, GA 30602, USA. Electronic address: [email protected].

PMID: 41129951
DOI: 10.1016/j.jinorgbio.2025.113093

Free article

Progesterone receptor membrane component 1 (PGRMC1) regulates Heme trafficking through mitochondria-ER junctions

Robert B Piel Iii et al. J Inorg Biochem. 2025.

Free article

. 2025 Oct 7:275:113093.

doi: 10.1016/j.jinorgbio.2025.113093. Online ahead of print.

Authors

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
² Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA.
³ School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112, USA.
⁶ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁷ Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁸ Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
⁹ Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
¹⁰ School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
¹¹ Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA; Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA.
¹² Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA; Department of Interdisciplinary Biomedical Sciences, University of Georgia School of Medicine, Athens, GA 30602, USA. Electronic address: [email protected].

PMID: 41129951
DOI: 10.1016/j.jinorgbio.2025.113093

Abstract

Heme is a cofactor essential for a multitude of biological reactions. The terminal step of heme synthesis occurs in the mitochondrial matrix which means that heme must be trafficked from there to other locales in the cell. Thus, identifying intracellular heme chaperones is crucial to understanding regulation of global cellular metabolism. The heme-binding protein progesterone receptor membrane component 1 (PGRMC1) has been proposed to function as a chaperone for several biologically active molecules including heme, but its cellular role is not fully understood. Here, we investigate the function of PGRMC1 in heme metabolism. By monitoring intracellular heme location and concentrations in Saccharomyces cerevisiae, we show that mutants lacking damage associated protein 1 (Dap1), the yeast ortholog of PGRMC1, have altered nuclear heme trafficking which can be corrected by complementation with DAP1 or PGRMC1. Biochemical analyses reveal that PGRMC1 co-localizes with known mitochondrial-associated membrane (MAM) proteins and proteomic comparison of interaction partners shows enrichment of MAM-associated proteins and pathways. Metabolomics profiling of wild-type and PGRMC1 knockout cells identifies significant changes of several metabolites, including heme, several amino acids, long chain acyl-carnitine, ethanolamine phosphate, and mevalonic acid. Together, these results provide evidence that PGRMC1 is involved in heme trafficking and homeostasis through MAMs.

Keywords: Ferrochelatase; Heme; MAMs; Mitochondria; PGRMC1.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amy E. Medlock reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Progesterone receptor membrane component 1 (PGRMC1) regulates Heme trafficking through mitochondria-ER junctions

Affiliations

Progesterone receptor membrane component 1 (PGRMC1) regulates Heme trafficking through mitochondria-ER junctions

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials