Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia

Navarro, Juan Antonio Micó; Botella, J; Metzendorf, Christoph; Lind, Maria; Schneuwly, Stephan

doi:10.1016/j.freeradbiomed.2015.03.014

Cited by 53 publications

(61 citation statements)

References 74 publications

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“…Interestingly, co-expression in the glia of frataxin-deficient flies of Glaz, one of the Drosophila homologs of apolipoprotein D (ApoD), was sufficient to increase the lifespan and improve locomotor activity, likely due to its modulation of lipid composition and oxidation. The same authors later demonstrated that also an enhanced iron transport inside mitochondria was involved in the degenerative phenotype induced by frataxin depletion, as demonstrated by the fact that a reduction of mitoferrin, a mitochondrial iron transporter, significantly improved the motor impairments, while its overexpression enhanced them [115]. Further, Loria and colleagues [61] reported that frataxin-depleted cultured human astrocytes had altered mitochondrial morphology and suffered great oxidative stress, therefore supporting the idea that an increased mitochondrial iron content favors astrocytes oxidative stress.…”

Section: When Astrocytes "Burn Out": Stressed Astrocytes Cause Accumumentioning

confidence: 91%

“…Along the same line, apolipoprotein D may provide an important therapeutic target, due to its modulation of lipid composition and lipid oxidation, as hinted by evidences obtained in a Drosophila model of FA [59]. On the other side, counteracting iron transport inside mitochondria may be another promising option to slow down neuronal degeneration in FA, and this could be achieved through mitoferrin depletion or iron chelation therapies [115,122]. Last, insulin-like growth factor I (IGF-I) injections were shown to protect neurons from frataxin deficiency in a non-cell autonomous fashion, both enhancing frataxin levels in astrocytes and potentiating their neuroprotective properties through the stimulation of the Akt/mTOR pathway [123].…”

Section: Treating Astrocytes To Heal Neurons: New Promising Approachementioning

confidence: 97%

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Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato

2020

JCM

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Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at the tissue level, by cerebellar atrophy and Purkinje cells degeneration. For this reason, the contribution of astrocytes to this disease has been largely overlooked in the past. Nevertheless, in the last few decades, growing evidences are pointing to cerebellar astrocytes as crucial players not only in the progression but also in the onset of distinct forms of ataxia. Although the current knowledge on this topic is very fragmentary and ataxia type-specific, the present review will attempt to provide a comprehensive view of astrocytes’ involvement across the distinct forms of this pathology. Here, it will be highlighted how, through consecutive stage-specific mechanisms, astrocytes can lead to non-cell autonomous neurodegeneration and, consequently, to the behavioral impairments typical of this disease. In light of that, treating astrocytes to heal neurons will be discussed as a potential complementary therapeutic approach for ataxic patients, a crucial point provided the absence of conclusive treatments for this disease.

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Section: When Astrocytes "Burn Out": Stressed Astrocytes Cause Accumumentioning

confidence: 91%

Section: Treating Astrocytes To Heal Neurons: New Promising Approachementioning

confidence: 97%

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato

2020

JCM

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“…Indeed, down regulation of increased mitoferrin expression reversed mitochondrial iron accumulation and ameliorated nervous system degeneration in a Drosophila model of Friedreich’s ataxia [30]. In general, the mitochondrial iron deposits in these syndromes contain oxidized iron [31], though iron is sometimes found in mitochondrial ferritin, an iron storage molecule [32] [33] [34].…”

Section: The Mystery Of Mitochondrial Iron Overload Diseases- How Is mentioning

confidence: 99%

“…Since mitoferrin expression clearly increases in several models of Friedrich’s ataxia [35] [30] and ISCU myopathy [28], nuclear remodeling of transcription of critical mitochondrial iron homeostasis genes seems to be the mechanism for coordinating the increase in mitochondrial iron concentrations. Greater understanding could have important implications for numerous human diseases that are not readily treatable at this point.…”

Section: Conclusion- What Is the Pathophysiology Of Mitochondrial Irmentioning

confidence: 99%

Mitochondrial iron overload: causes and consequences

Rouault

2016

Current Opinion in Genetics & Development

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Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified.

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“…The respiratory chain electron transporters involving complex I-III are inhibited, resulting in decreased energy production and increased free radical formation [91] which may ultimately lead to oxidative stress-induced activation of the intrinsic apoptotic pathway [92]. Frataxin-deficient flies are hypersensitive to increased dietary iron uptake, but their mitochondrial function can be restored by inhibiting the mitochondrial iron uptake via mitoferrin [93]. The most severely affected organs are heart, cerebellum, and spinal cord, especially dorsal root ganglia [94].…”

Section: Friedreich's Ataxiamentioning

confidence: 99%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

103

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia

Cited by 53 publications

References 74 publications

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Mitochondrial iron overload: causes and consequences

Iron chelation in the treatment of neurodegenerative diseases

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