mitochondrail iron trafficking

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Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol:

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

What the topic is concerned?:

What the topic is concerned? Basics of iron metabolism, Proteins involved in signaling and tranport , Role of mitochondria in iron metabolism, How mitochondria drives the cellˈs iron uptake, Need for chaperones for Fe3† Disorders of mitochondrial iron metabolism

Cellular Iron Metabolism and Transport:

Cellular Iron Metabolism and Transport Two forms of iron: 1. soluble iron(II )( relatively ) 2. insoluble ferric hydroxides Because of its insolubility and potential toxicity iron must be constantly chaperoned Iron is specifically transported in blood by differic transferrin ( Tf )

Receptors and proteins involved:

Receptors and proteins involved Transferrin receptor 1 (TfR1) MRCK α ( myotonic dystrophy kinase -related Cdc42-binding kinase alpha ) Iron regulatory protein(IRP) Iron responsive element(IRE) Sec15l1 Rab11

Cellular iron uptake:

Cellular iron uptake

Regulation of Cellular Iron Homeostasis:

Regulation of Cellular Iron Homeostasis

“Kiss and run” hypothesis:

“Kiss and run” hypothesis

Regulation of iron uptake:

Regulation of iron uptake IRP-IRE mechanisms Frataxin mutation of its gene leads to targeting of iron towards the mitochondrion leading to relative deficiency in cytosol . Also there is over expression of mitochondrial ferritin Ftmt , again that leads to mitochondrial iron loading Similar mitochondrondrial iron loading occurs in Isu splice mutation and glutaredoxin deficiency

Mitochondrial Iron Import:

Mitochondrial Iron Import SLC25A37(mitoferrin-1) erythroid cells. SLC25A28(mitoferrin-2 ) ubiquitously. These are transporters of iron present in inner mitochondrial membrane. Abcb10 they are found interacting with mitoferrin-1 this interaction increases mitochondrial iron import. Abcb10 is rapidly induced by transcriptional factor GATA1 ,which has role in erythroid differntiation Transport across outer membrane is still unknown three potential transporters that may be involved are SLC25A39, SLC22A4 and TMEM14C

Mitochondrial iron storage:

Mitochondrial iron storage Ftmt (mitochondrial ferrtin ) Similar to ferritin in all respects Encoded by an atypical intronless gene Detected in heart, brain, spinal cord,kidney & pancreas Most abundant in testes and erythroblasts. Not highly expressed in liver and spleen FUNCTION: Protection from iron-dependant oxidative damage Increases IRP-1/2 -RNA binding activity Decreases cytosolic and mitochondrial aconitase

Iron sulfur synthesis:

Iron sulfur synthesis Serves as cofactor s of proteins in electron transport, Requires both mitochondrial and cytosolic machinery, First molecule identified is Nfs1 a cysteine desulfurase , Iscu1 and 2 ISC assembly proteins, ABCB7 mediates cytosolic ISC synthesis, Mutation in ABCB7 leads to XLSA/A.

Heme synthesis:

Heme synthesis

Heme synthesis:

Heme synthesis Pathway consists of eight sequential steps, First and last three steps takes place in mitochondria. First enzyme : 5 -aminolevulinate synthase . Two genes ALAS1 and ALAS2 ( erythroid specific), Non erythroid cells (rate of ALA synthesis), Erythroid cells (delivery of Tf iron) Last three steps: Coproporphyrinogen may be carried to mitochondria by either peripheral-type benzodiazepine receptors or potentially by ABCB6

Mitochondrial iron exporters:

Mitochondrial iron exporters Mammalian mitochondrial ABC protein 3 MTABC3 ABCB7 ISCs to cytosol Heme binding protein 1 transports heme out to cytosol , its expression is increased during erythroid differentiation. Hbp-1 binds one heme per one mole of protein

Metabolic role of frataxin:

Metabolic role of frataxin

Frataxin and iron storage:

Frataxin and iron storage Yfh1 Frataxin ortholog of yeast. Iron dependant assembly into oligomers and multimers , Oligomeric / multimeric frataxin has feroxidase activity Oligomersation occurs only in absence of Ca2+ and Mg2+ Points against this function: Mitochondria is typically abundant in Ca2+ and Mg2+ No iron dependant oligomerisation seen Mitochondrial ferritin has been identified to this function

Frataxin as an iron chaperone:

Frataxin as an iron chaperone Most promising emerging role. YFH1 interacts with central ISC assembly complex. Interacts with Isu1 via highly conserved W131a residue, Interaction with Isu1 enhances ISC synthesis, Interaction with ferrochelatase increases heme synthesis.

Frataxin as an iron sensor:

Frataxin as an iron sensor Negatively regulates the ISC bisosynthesis . When there is low levels ISC apo -acceptor and high iron levels, frataxin exerts a “kinetic control”. In the absence of frataxin this kinetic control is absent leads to the over production of unstable ISCs. Whether such kinetic control for frataxinˈs interaction with ferrochelatase exists is still unknown.

Frataxin as a metabolic switch:

Frataxin as a metabolic switch Erythroid differentiation downregulates frataxin . Immediate precursor of heme PPIX downregulates frataxin . Diversion of iron from all other parhways to heme synthesis Thus according to expression levels relative to Isu or ferrochelatase , frataxin allows metobolic switching between ISC or heme synthesis.

Sideroblastic anemia:

Sideroblastic anemia Proposed factors: Iron specifically targeted to erythroid mitochondrias Lack of PPIX Lack of heme Lack of iron insertion into PPIX Known mutations: XLSA / A-mutations in ABCB7 RARS -mutations in cytochrome oxidase Glycine transporter ( SLC25A38 ) mutations Mutations of pseudouridine synthase-1

conclusion:

conclusion Mitochondrion can modulate cellular iron uptake for its demand. Signaling pathways exists between cytosol and mitochondrial iron processing machinery. Perspectives: Exact role of frataxin , Iron transporters across outer mitochondrial membrane, Transporters moving out iron.

Slide 26:

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