Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in <i>Drosophila</i>

Runko, Alexander Peter; Griswold, Anthony J.; Min, Kyung‐Tai

doi:10.1016/j.febslet.2008.01.046

Cited by 65 publications

(56 citation statements)

References 28 publications

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“…It is now widely accepted that mitochondria are a major source of ROS and a major site of ROS-induced oxidative damage, and that ROS production increases with age [36,38]. The theory is supported by the observations that over-expressing the mitochondrial antioxidant gene MnSOD [39] or the mitochondrial iron regulator protein frataxin [40] significantly increases longevity in Drosophila, while over-expressing a mitochondriallytargeted catalase gene results in reduced age-related pathology and moderately increased lifespan in mice [41]. Oxidative damage caused by ROS is also postulated to play a role in AHL [4,21,22].…”

Section: Delay Of Age-related Hearing Loss By Crsupporting

confidence: 50%

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Someya¹,

Tanokura²,

Weindruch³

et al. 2010

CAS

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Age-related hearing loss (AHL), also known as presbycusis, is a universal feature of mammalian aging and is the most frequently occurring sensory disorder in the elderly population. AHL is characterized by a decline of auditory function and loss of hair cells and spiral ganglion neurons in the cochlea of the inner ear. It has been postulated that AHL occurs gradually as a result of the cumulative effect with aging of exposure to noise, diet, oxidative damage, and mitochondrial DNA mutations. However, the molecular mechanisms of AHL remain unclear and no preventative or therapeutic interventions have been developed. A growing body of evidence suggests increased oxidative damage with aging to macromolecules such as DNA, proteins, and lipids may play a causal role in aging and age-related diseases. Caloric restriction (CR) extends the lifespan of most mammalian species, delays the onset of multiple age-related diseases, and attenuates both the degree of oxidative damage and the associated decline in physiological function. Here, we review studies on CR's ability to prevent cochlear pathology and AHL in laboratory animals and discuss potential molecular mechanisms of CR's actions.

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Section: Delay Of Age-related Hearing Loss By Crsupporting

confidence: 50%

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Someya¹,

Tanokura²,

Weindruch³

et al. 2010

CAS

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show abstract

“…In addition, deficiency of frataxin, which is involved in mitochondrial Fe-S biogenesis, is characterized by hypertrophic cardiomyopathy and heart failure (107). Interestingly, overexpression of frataxin leads to increased mitochondrial membrane potential, elevated ATP levels, resistance to oxidative stress, and life span extension (108,109), defects which are characteristic of CL deficiency (7). In transgenic mice, overexpression of frataxin counteracted cardiotoxic stress, preventing cardiomyopathy and cardiac failure (110).…”

Section: Discussionmentioning

confidence: 99%

Loss of Cardiolipin Leads to Perturbation of Mitochondrial and Cellular Iron Homeostasis

Patil

Fox

Gohil

et al. 2013

Journal of Biological Chemistry

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“…[3][4][5][6][7][8] Furthermore, complete absence of FXN leads to early embryonic lethality in transgenic mice. Conditional FXN knockout strains for striated muscles and neuron/cardiac muscles reproduce progressive pathophysiological and biochemical features of the human disease and demonstrate timedependent intramitochondrial iron accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…3,4,15,16 Retinal ischemia/hypoxia is a complication of ocular diseases such as diabetic retinopathy, retinopathy of prematurity, and glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Schultz

Witte

Schmeer

2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Schultz R, Witte OW, Schmeer C. Increased frataxin levels protect retinal ganglion cells after acute ischemia/reperfusion in the mouse retina in vivo. Invest Ophthalmol Vis Sci. 2016;57:4115-4124. DOI:10.1167/iovs.16-19260 PURPOSE. The mitochondrial protein frataxin (FXN) is highly expressed in metabolically active tissues and has been shown to improve cell survival in response to oxidative stress after ischemia. Retinal ischemia/hypoxia is a complication of ocular diseases such as diabetic retinopathy and glaucoma. There are no effective therapeutic approaches currently available. This study was performed to evaluate the neuroprotective effects of FXN after acute retinal ischemia/reperfusion in vivo. METHODS.Retinal ischemia/reperfusion was induced in adult wild-type and FXN-overexpressing mice by transient elevation of intraocular pressure (IOP) for 45 minutes. Expression of FXN was evaluated by quantitative (q)RT-PCR and Western blot analysis between 6 and 48 hours after ischemia. Retinal ganglion cell (RGC) survival was determined with immunofluorescent staining and fluorescence microscopy 14 days after lesion. Expression of hypoxiainducible factors Hif-1a and Hif-2a and of oxidative stress markers heme oxygenase-1 (Hmox1), glutathione peroxidase 1 (Gpx1), superoxidase dismutase 1 and 2 (Sod1, Sod2), and catalase was evaluated by qRT-PCR.RESULTS. Endogenous FXN levels were upregulated for up to 24 hours after retinal ischemia in vivo. Retinal ganglion cell survival was significantly improved in FXN-overexpressing mice 14 days after ischemia. Expression of antioxidative enzymes Gpx1, Sod2, and catalase was significantly increased in FXN-overexpressing mice after lesion. CONCLUSIONS.Retinal FXN levels are increased in response to ischemia. Furthermore, elevated FXN levels had a clear neuroprotective effect as shown by increased ganglion cell survival after acute retinal ischemia/reperfusion. Frataxin's neuroprotective effect was associated with an upregulation of antioxidative enzymes. The data suggest that FXN induces neuroprotection by decreasing oxidative stress.Keywords: frataxin, retinal ischemia, retinal ganglion cell, antioxidants F rataxin (FXN) is a nuclear-encoded mitochondrial protein highly conserved among eukaryotes. The mouse gene (Frda) encodes a 207-amino acid protein showing 73% amino acid identity to its human counterpart.1 It is abundantly expressed in metabolically active tissues such as liver, skeletal and cardiac muscle, and brain.1 In the retina of normal mice, immunoreactivity to FXN is found in the external and internal plexiform layers, the ganglion cell layer, and the inner nuclear layer.2 Frataxin deficiency is closely related to Friedreich ataxia (FRDA), a neurodegenerative disease associated with abnormal influx of iron into the mitochondria, which increases the susceptibility of the nervous system to oxidative stress. [3][4][5][6][7][8] Furthermore, complete absence of FXN leads to early embryonic lethality in transgenic mice. Conditional FXN knockout strains for st...

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Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila

Cited by 65 publications

References 28 publications

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Effects of Caloric Restriction on Age-Related Hearing Loss in Rodents and Rhesus Monkeys

Loss of Cardiolipin Leads to Perturbation of Mitochondrial and Cellular Iron Homeostasis

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

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