Actin Modulates the Gating of Neurospora crassa VDAC

Xu, Xiaofeng; Forbes, Jeffrey G.; Colombini, Marco

doi:10.1007/s002320010060

Cited by 95 publications

(71 citation statements)

References 37 publications

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“…This scenario seems to reconcile the defects at the level of cytoskeletal organization (1), mitochondrial network (20) and bioenergetics (20,21,24) described in cells from premutation carriers. Furthermore, considering that FMRP regulates the organization and dynamics of actin filaments (50,51), a key process in the morphogenesis of dendritic spines (50), and that actin seems to be involved in mitochondria function and dynamics (48,(52)(53)(54)(55)(56)(57), it could be hypothesized that altered cytoskeletal organization-as a Novartis, Roche/Genentech and Zynerba regarding treatment for fragile X syndrome. formation, inhibits Kreb's cycle, favors ketogenesis and lipogenesis from excess of acetylCoA that did not enter the Kreb's cycle.…”

Section: Resultsmentioning

confidence: 99%

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Song¹,

Napoli²,

Wong³

et al. 2016

Mol Med

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A 55-200 expansion of the CGG nucleotide repeat in the 5′-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with age-and sex-matched controls (n = 25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTASaffected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome-and/or carrierspecific. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset. online address: http://www.molmed.org

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Section: Resultsmentioning

confidence: 99%

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Song¹,

Napoli²,

Wong³

et al. 2016

Mol Med

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“…It has also been shown that in neuronal cells the antiapoptotic activity of gelsolin is actin dependent (Harms et al, 2004). In vitro studies have also demonstrated that actin can influence VDAC closure in Neurospora crassa (Xu et al, 2001). However, in our studies, the overexpression of the antiapoptotic proteins Bcl-2 or BclxL, which are known to regulate VDAC closure, in ∆end3 cells have no effect on H 2 O 2 sensitivity or culture viability (C.W.G.…”

Section: Discussionmentioning

confidence: 97%

Identification of an upstream regulatory pathway controlling actin-mediated apoptosis in yeast

Gourlay

Ayscough

2005

Journal of Cell Science

119

109

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The build up of reactive oxygen species (ROS) is known to contribute to a reduction in the lifespan of a cell and to their degeneration in diseases such as Alzheimer's and tissue ischaemia. It is therefore important to elucidate pathways that regulate cellular oxidative stress. We have previously shown that actin dynamics can affect the oxidative-stress burden on a yeast cell and thereby its potential lifespan. To elucidate further the connection between actin dynamics and oxidative stress, we sought to identify regulators of this process. The actin regulatory proteins Sla1p and End3p are important in maintaining a rapid turnover of F-actin in cortical patches. We show that cells expressing a mutated form of Sla1p or lacking End3p display markers of apoptosis such as depolarized mitochondrial membranes and elevated levels of reactive oxygen species. Overexpression of the ubiquitin ligase RSP5 can alleviate the oxidative-stress phenotype observed in cells lacking End3p by targeting Sla1p to the cortex and restoring actin remodelling capability. We also demonstrate that overexpression of PDE2, a negative regulator of the Ras/cAMP pathway rescues actin dynamics, reduces oxidative stress sensitivity and restores viability in Δend3 cells. Our data suggest, for the first time, that a physiological link exists between actin regulation and cAMP signalling that regulates apoptosis in yeast.

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“…Taken together, these results suggest that the contact site may be involved in the import of actin from the cytosol, and actin dynamics at the contact site may affect the opening and closure status of the mPTP. Actin has been shown to be capable of modulating the gating process in Neurospora crassa voltage-dependent anion channel (VDAC) (Xu et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Actin in Mung Bean Mitochondria and Implications for Its Function

Cheng

Hsiao

et al. 2011

The Plant Cell

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Here, a large fraction of plant mitochondrial actin was found to be resistant to protease and high-salt treatments, suggesting it was protected by mitochondrial membranes. A portion of this actin became sensitive to protease or high-salt treatment after removal of the mitochondrial outer membrane, indicating that some actin is located inside the mitochondrial outer membrane. The import of an actin-green fluorescent protein (GFP) fusion protein into the mitochondria in a transgenic plant, actin:GFP, was visualized in living cells and demonstrated by flow cytometry and immunoblot analyses. Polymerized actin was found in mitochondria of actin:GFP plants and in mung bean (Vigna radiata). Notably, actin associated with mitochondria purified from early-developing cotyledons during seed germination was sensitive to high-salt and protease treatments. With cotyledon aging, mitochondrial actin became more resistant to both treatments. The progressive import of actin into cotyledon mitochondria appeared to occur in concert with the conversion of quiescent mitochondria into active forms during seed germination. The binding of actin to mitochondrial DNA (mtDNA) was demonstrated by liquid chromatography-tandem mass spectrometry analysis. Porin and ADP/ATP carrier proteins were also found in mtDNA-protein complexes. Treatment with an actin depolymerization reagent reduced the mitochondrial membrane potential and triggered the release of cytochrome C. The potential function of mitochondrial actin and a possible actin import pathway are discussed.

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Actin Modulates the Gating of Neurospora crassa VDAC

Cited by 95 publications

References 37 publications

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Identification of an upstream regulatory pathway controlling actin-mediated apoptosis in yeast

Actin in Mung Bean Mitochondria and Implications for Its Function

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