From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme
Abstract
1. Introduction
2. Heme Biosynthesis
2.1. ALA Production
2.2. CPgenIII Formation
2.3. Coproporphyrinogen Oxidase (CPOX) and Protoporphyrinogen Oxidase (PPOX)
2.4. Ferrochelatase
2.5. Anemias and Porphyrias
3. From Heme b to Hemes c, o and a
3.1. Mitochondrial Heme b Pathways
3.2. Heme c Pathway
3.3. Heme a Pathway
3.3.1. Heme o Synthase
3.3.2. Heme a Synthase
3.3.3. Other Proteins Related to Heme a Biogenesis
3.4. Heme c and Heme a Pathway-Related Diseases
4. Extra-Mitochondrial Heme Trafficking
4.1. Exit of Mitochondrial Heme
4.2. Import of Exogenous Heme
4.3. Exogenous vs. Endogenous Heme
4.4. Heme Trafficking Factors
5. Multi-Model Comparison of Eukaryotic Heme Homeostasis
6. New Methods to Probe Heme Trafficking
7. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CO | Carbon monoxide |
IMS | Mitochondrial intermembrane space |
TCA | Tricarboxic acid |
IMM | Inner mitochondrial membrane |
5-ALA | 5-aminolevulunic acid |
ALAS | Aminolevulunic acid synthase |
PBGS | Porphobilinogen synthase |
PBG | Porphobilinogen |
HMB | Hydroxymethylbilane |
HMBS | Hydroxymethylbilane synthase |
UPgen III | Uroporphyrinogen III |
UROS | Uroporphyrinogen synthase |
CPgen III | Coproporphyrinogen III |
UROD | Uroporphyrinogen decarboxylase |
PPgen IX | Protoporphyrinogen IX |
CPOX | Coproporphyrinogen oxidase |
Fe-PPIX | Iron-protoporphyrin IX |
PPIX | Protoporphyrin IX |
PPOX | Protoporphyrinogen oxidase |
FECH | Ferrochelatase |
PLP | Pyridoxal 5’-phosphate |
OMM | Outer mitochondrial membrane |
SLC | Solute carrier |
α-KG | A-ketoglutarate |
MTS | Mitochondria-targeting sequence |
HRM | Heme regulatory motif |
IRP | Iron regulatory protein |
ATP | Adenosine triphosphate |
ADP | Adenosine diphosphate |
AAA+ | ATP hydrolase associate with various cellular activities |
ANT | Adenine nucleotide translocator |
KDH | A-ketoglutarate dehydrogenase |
CcO | Cytochrome c oxidase |
ETC | Electron transport chain |
SDH | Succinate dehydrogenase |
CCHL | Cytochrome c heme lyase |
HCCS | Holocytochrome c synthase |
MLS | Microphthalmia with linear skin defects |
TMD | Transmembrane domain |
FDX | Ferredoxin |
MAMs | Mitochondria-associated membranes |
ERMES | Endoplasmic reticulum-mitochondria encounter structure |
MDV | Mitochondrial-derived vesicle |
HRG | Heme responsive gene |
ZnMP | Zinc mesoporphyrin |
CHO | Chinese hamster ovary |
LDL | Low-density lipoprotein |
HDL | High-density lipoprotein |
HO | Heme oxygenase |
FeLV | Feline leukemia virus |
ABC | ATP-binding cassette |
BRCP | Breast cancer resistance protein |
HBP | Heme-binding protein |
FABP | Fatty acid-binding protein |
GAPDH | Glyceraldehyde phosphate dehydrogenase |
PGRMC1/2 | Progesterone receptor membrane component 1/2 |
EGFP | Enhanced green fluorescent protein |
ECFP | Enhanced cyan fluorescent protein |
EYFP | Enhanced yellow fluorescent protein |
HS | Heme sensor |
FRET | Forster resonance energy transfer |
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Heme Homeostatic Process | Enzyme | Saccharomyces cerevisiae | Caenorhabditis elegans | Homo sapiens |
---|---|---|---|---|
Heme Synthesis | 5-aminolevulinic acid synthase | Hem1 | ✖ | ALAS1/ALAS2 |
Porphobilinogen synthase | Hem2 | ✖ | PBGS | |
Hydroxymethylbilane synthase | Hem3 | ✖ | HMBS | |
Uroporphyrinogen synthase | Hem4 | ✖ | UROS | |
Uroporphyrinogen decarboxylase | Hem12 | ✖ | UROD | |
Coproporphyrinogen oxidase | Hem13 | ✖ | CPOX | |
Protoporphyrinogen oxidase | Hem14 | ✖ | PPOX | |
Ferrochelatase | Hem15 | fecl-1 | FECH | |
Heme Degradation | Heme oxygenase | Hmx1 | ? | Hmox1/Hmox2 |
Heme Import | FLVCR2 | ✖ | ✔ | ✔ |
HRG4 | ✖ | ✔ | ✖ | |
Heme Export | FLVCR1 | ✖ | ✖ | ✔ |
MRP5 | ✖ | mrp-5 | ABCC5 | |
Pug1 | ✔ | ✖ | ✖ | |
HRG3 | ✖ | ✔ | ✖ | |
Heme Trafficking | PGRMC1/2 | Dap1 | vem-1 | PGRMC1/2 |
GAPDH | Tdh1/2/3 | gpd1/2/3/4 | GAPDH | |
HRG1 | ✖ | ✔ | ✔ |
Approaches | Methods | Advantages | Disadvantages |
---|---|---|---|
In Situ Label Free Imaging | Transient Absorption Microscopy Resonance Raman Imaging 2 Photon Photothermal Lens Microscopy | Subcellular resolution (<1 μm) Non-invasive Can probe heme dynamics in living cells | Signals dominated by most abundant and/or highly absorbing species Low-throughput Requires specialized equipment/expertise |
In Situ Imaging of Labile Heme using Fluorescent Heme Sensors | HS1 CISDY-9 CHY | Subcellular resolution (<1 μm) Direct probe of labile “bioavailable” heme Can probe heme dynamics in living cells High-throughput | May perturb heme homeostasis Possible selection bias depending on the nature of the sensor Extended time resolved studies precluded by photobleaching |
Assays for Endogenous Markers of Heme Bioavailability | Horseradish Peroxidase Tryptophan 2,3 Dioxygenase (TDO) Indoleamine-2,3-Dioxygenase (IDO) Cytochrome P450 Catalase Transcription Factors | Measurement of heme accessible to endogenous hemoproteins No genetic perturbations | Disruption of cells and tissues Time consuming Difficult to get fast time resolution |
Assays for Total Heme | HPLC | Resolve different heme types | Time consuming Disruption of cells and tissues Low-throughput |
Porphyrin Fluorescence | nM sensitivity High-throughput | Disruption of cells and tissues | |
UV/vis Absorbance Spectroscopy | CLARiTY | Sensitive measurements in turbid samples Possible to measure heme and hemoproteins in intact cells | Signals dominated by most abundant and/or highly absorbing species Low-throughput Requires specialized equipment |
Pyridine Hemochromagen | Broadly accessible Inexpensive | Disruption of cells and tissues |
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Swenson, S.A.; Moore, C.M.; Marcero, J.R.; Medlock, A.E.; Reddi, A.R.; Khalimonchuk, O. From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme. Cells 2020, 9, 579. https://doi.org/10.3390/cells9030579
Swenson SA, Moore CM, Marcero JR, Medlock AE, Reddi AR, Khalimonchuk O. From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme. Cells. 2020; 9(3):579. https://doi.org/10.3390/cells9030579
Chicago/Turabian StyleSwenson, Samantha A., Courtney M. Moore, Jason R. Marcero, Amy E. Medlock, Amit R. Reddi, and Oleh Khalimonchuk. 2020. "From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme" Cells 9, no. 3: 579. https://doi.org/10.3390/cells9030579
APA StyleSwenson, S. A., Moore, C. M., Marcero, J. R., Medlock, A. E., Reddi, A. R., & Khalimonchuk, O. (2020). From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme. Cells, 9(3), 579. https://doi.org/10.3390/cells9030579