Mitochondrial Iron in Human Health and Disease

Ward, Diane M.; Cloonan, Suzanne M.

doi:10.1146/annurev-physiol-020518-114742

Cited by 131 publications

(99 citation statements)

References 177 publications

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“…2f). Mitochondria are a major site of cellular iron storage and utilization in processes such as heme synthesis and iron-sulfur cluster biogenesis 58 . Disruption of the electron transport chain may lead to mitochondrial damage which can cause the subsequent release of labile iron and reduced iron utilization, thus increasing labile iron levels.…”

Section: Genome-wide Crispri/a Screens Elucidate Pathways Controllingmentioning

confidence: 99%

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Tian

Abarientos

Hong

et al. 2020

Preprint

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SUMMARYSingle-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here, we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons.We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons following perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

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Section: Genome-wide Crispri/a Screens Elucidate Pathways Controllingmentioning

confidence: 99%

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Tian

Abarientos

Hong

et al. 2020

Preprint

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“…Mitochondria, the main subcellular organelles for energy metabolism in eukaryotes, play extremely important roles in several physiological and pathological processes (1). Mitochondrial dysfunction mainly refers to an energy metabolism disorder caused by various factors including dissipation of the mitochondrial membrane, inhibition of the respiratory chain, reduction in enzyme activity, and mitochondrial DNA (mtDNA) damage, which can lead to a number of diseases including cancer (1). Mitochondrial functions are also regulated by mitochondrial dynamics (2,3).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‑induced mitochondrial translocation of DNM1L increases mitochondrial fission and triggers mPTP opening in HCC cells via activation of HK2

Cai

Fang

2019

Oncol Rep

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Disturbed mitochondrial dynamics are closely associated with the progression of different types of cancer including hepatocellular carcinoma (HCC). However, the manner in which mitochondrial dynamics are regulated in HCC remains largely unclear. In the present study, via immunofluorescence, real-time PCR and western blot analysis, the effects of dynamin-1-like (DNM1L) on mitochondrial translocation and the mitochondrial permeability transition pore (mPTP) were investigated in HCC cells under hypoxic conditions, and the underlying molecular mechanisms were explored. Our data revealed that hypoxic treatment decreased the mitochondrial membrane potential, elevated generation of reactive oxygen species, and promoted mitochondrial fission in a DNM1L-dependent manner. Instead of changing the levels of DNMlL, hypoxia increased the translocation of DNM1L to mitochondria, leading to excessive mitochondrial fission and decreased the viability of HCC cells. In addition to the effects on mitochondrial dynamics, DNM1L also regulated mPTP opening in HCC. IP analysis revealed that DNM1L interacted with the enzyme hexokinase 2 (HK2), and was involved in its phosphorylation, resulting in HK2 detachment from the mitochondria and consequently mPTP opening.

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“…In human cells silenced for both mitoferrin-1 and -2, mitochondrial iron transport was found to be reduced more than 90%, suggesting that mitoferrins contribute to most of the mitochondrial iron supply [ 196 , 197 ]. In human erythroid cells, the loss of mitoferrin-1 could induce heme synthesis defects due to impaired mitochondrial iron uptake [ 194 , 198 , 199 ], causing erythropoietic protoporphyria [ 200 , 201 ]. Moreover, the knockdown of mitoferrin-2 resulted in a decreased mitochondrial iron content in human epithelial cell lines [ 64 ], and its depletion in murine fibroblasts affected heme synthesis and mitochondrial Fe/S cluster assembly [ 202 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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Mitochondrial Iron in Human Health and Disease

Cited by 131 publications

References 177 publications

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Hypoxia‑induced mitochondrial translocation of DNM1L increases mitochondrial fission and triggers mPTP opening in HCC cells via activation of HK2

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

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