Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology

Amorim, Inês S.; Graham, Laura C.; Carter, Roderick N.; Morton, Nicholas M.; Hammachi, Fella; Kunath, Tilo; Pennetta, Giuseppa; Carpanini, Sarah M.; Manson, Jean; Lamont, Douglas J.; Wishart, Thomas M.; Gillingwater, Thomas H.

doi:10.1242/jcs.194241

Cited by 26 publications

(44 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Instead, the transmembrane domains of SFXN2 functioned as a mitochondrial targeting signal and guided SFXN2 to the mitochondria. In contrast to SFXN2, SFXN3, and SFXN4 are targeted to the inner mitochondrial membrane [ 33 , 34 ]. Sequence homology is 54% between SFXN2 and SFXN3, but only 20% between SFXN2 and SFXN4 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although the molecular functions of Sfxn proteins are unclear, recent studies demonstrated that these proteins are involved in physiological functions and disease. For example, Sfxn3 has been implicated in the differentiation of pancreatic islets in mice and the regulation of synaptic morphology at neuromuscular junctions in Drosophila [ 32 , 33 ]. Pathogenic mutations of the SFXN4 gene have been identified in mitochondrial disease patients with macrocytic anemia [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of mitochondrial iron homeostasis by sideroflexin 2

et al. 2018

View full text Add to dashboard Cite

Mitochondrial iron is indispensable for heme biosynthesis and iron–sulfur cluster assembly. Several mitochondrial transmembrane proteins have been implicated to function in the biosynthesis of heme and iron–sulfur clusters by transporting reaction intermediates. However, several mitochondrial proteins related to iron metabolism remain uncharacterized. Here, we show that human sideroflexin 2 (SFXN2), a member of the SFXN protein family, is involved in mitochondrial iron metabolism. SFXN2 is an evolutionarily conserved protein that localized to mitochondria via its transmembrane domain. SFXN2 -knockout (KO) cells had an increased mitochondrial iron content, which was associated with decreases in the heme content and heme-dependent enzyme activities. By contrast, the activities of iron–sulfur cluster-dependent enzymes were unchanged in SFXN2 -KO cells. Moreover, abnormal iron metabolism impaired mitochondrial respiration in SFXN2 -KO cells and accelerated iron-mediated death of these cells. Our findings demonstrate that SFXN2 functions in mitochondrial iron metabolism by regulating heme biosynthesis. Electronic supplementary material The online version of this article (10.1007/s12576-018-0652-2) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of mitochondrial iron homeostasis by sideroflexin 2

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Proteomics analysis identified a series of α-syn interactors at the level of the IMM, including mitofilin, a mitochondrial inner membrane protein important for the regulation of cristae morphology ( John et al, 2005 ; McFarland et al, 2008 ). iTRAQ proteomics on synaptosomes from α-syn +/+ and α-syn -/- mice also revealed that α-syn interacts with sideroflexin 3 (SFXN3), a putative iron transporter of the IMM ( Fleming et al, 2001 ; Li et al, 2010 ) which is important for maintenance of the synaptic morphology and neuromuscular junctions ( Amorim et al, 2017 ) and that has been found down-regulated in substantia nigra of PD-affected patients ( Simunovic et al, 2009 ).…”

Section: Mitochondrial Routes For Alpha-synucleinmentioning

confidence: 99%

The Close Encounter Between Alpha-Synuclein and Mitochondria

et al. 2018

View full text Add to dashboard Cite

The presynaptic protein alpha-synuclein (α-syn) is unequivocally linked to the development of Parkinson’s disease (PD). Not only it is the major component of amyloid fibrils found in Lewy bodies but mutations and duplication/triplication in its gene are responsible for the onset of familial autosomal dominant forms of PD. Nevertheless, the precise mechanisms leading to neuronal degeneration are not fully understood. Several lines of evidence suggest that impaired autophagy clearance and mitochondrial dysfunctions such as bioenergetics and calcium handling defects and alteration in mitochondrial morphology might play a pivotal role in the etiology and progression of PD, and indicate the intriguing possibility that α-syn could be involved in the control of mitochondrial function both in physiological and pathological conditions. In favor of this, it has been shown that a fraction of cellular α-syn can selectively localize to mitochondrial sub-compartments upon specific stimuli, highlighting possible novel routes for α-syn action. A plethora of mitochondrial processes, including cytochrome c release, calcium homeostasis, control of mitochondrial membrane potential and ATP production, is directly influenced by α-syn. Eventually, α-syn localization within mitochondria may also account for its aggregation state, making the α-syn/mitochondria intimate relationship a potential key for the understanding of PD pathogenesis. Here, we will deeply survey the recent literature in the field by focusing our attention on the processes directly controlled by α-syn within mitochondrial sub-compartments and its potential partners providing possible hints for future therapeutic targets.

show abstract

“…Sfxn5 expression is high throughout the adult human brain compared to other tissues (Lockhart et al 2002). A developmental role for Sfxn3 is suggested from a study showing that Drosophila Sfxn3 mutants exhibit abnormal synaptic morphogenesis at the neuromuscular junction (Amorim et al 2017). Interestingly, Sfxn3 is a downstream target of α-synuclein, and may be involved in the neurodegenerative process in Parkinson’s disease (Amorim et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Sideroflexin 3 is a Mitochondrial Protein Enriched in Neurons

Rivell¹,

Petralia

Wang

et al. 2019

Neuromol Med

View full text Add to dashboard Cite

Sideroflexin 1 (Sfxn1) is a mitochondrial serine transporter involved in one-carbon metabolism in blood and cancer cell lines. The expression of other Sfxn homologs varies across tissues implying that each homolog may have tissue-specific functions. RNA databases suggest that among the Sfxns, Sfxn3 may have a specific function in the brain. Here, we systematically analyzed the level, cellular distribution, and subcellular localization of Sfxn3 protein in the developing and adult rodent brain. We found that, in the cortex and hippocampus, Sfxn3 protein level is low at birth but increases during development and remains at a high level in the mature brains. Similarly, in cultured hippocampal neurons, Sfxn3 protein level is low in young neurons but increases as neurons mature. Sfxn3 protein level is much higher in neurons than in astrocytes. Within neurons, Sfxn3 localizes to mitochondria in all major neuronal compartments. Our results establish that Sfxn3 is a mitochondrial protein enriched in neurons wherein it is developmentally expressed. These findings provide a foundation for future research aimed at understanding the functions of Sfxn3 and one-carbon metabolism in neurons.

show abstract

Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology

Cited by 26 publications

References 31 publications

Regulation of mitochondrial iron homeostasis by sideroflexin 2

Regulation of mitochondrial iron homeostasis by sideroflexin 2

The Close Encounter Between Alpha-Synuclein and Mitochondria

Sideroflexin 3 is a Mitochondrial Protein Enriched in Neurons

Contact Info

Product

Resources

About