Mitochondrial AIF protein involved in skeletal muscle regeneration

Qiu, Xiaozhong; Yu, Lei; Lai, Gui-Hua; Wang, Le‐yu; Chen, Bing; Ouyang, Jun

doi:10.1002/cbf.1483

Cited by 4 publications

(4 citation statements)

References 18 publications

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“…After cellular insult, AIF translocates to the nucleus and can cause cell death while also inducing classical apoptotic features such as phosphatidylserine exposure and chromatin condensation; this cell death mechanism has been shown to be PARP1-dependent in some systems, consistent with findings in Figure 5 [66-68]. This phenomenon of AIF induction after H 2 O 2 treatment has been reported in various cell types including B cells, myoblasts, and neurons, among others [68, 69]. Continuous influx of H 2 O 2 was seen to induce caspase-independent cell death in Jurkat T cells [70].…”

Section: Discussionsupporting

confidence: 74%

Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death

Evans

Tovmasyan

Batinić‐Haberle

et al. 2014

Free Radical Biology and Medicine

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Resistance to therapy-mediated apoptosis in inflammatory breast cancer (IBC), an aggressive and distinct subtype of breast cancer, was recently attributed to increased superoxide dismutase (SOD) expression, glutathione (GSH), and decreased accumulation of reactive species. In the present study, we demonstrate the unique ability of two Mn(III) N-substituted pyridylporphyrin (MnP)-based SOD mimics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+) to catalyze oxidation of ascorbate, leading to the production of excessive levels of peroxide and in turn cell death. The accumulation of peroxide, as a consequence of MnP + ascorbate treatment, was fully reversed by the administration of exogenous catalase showing that ROS was essential for cell death. Cell death as a consequence of the action of MnP/ascorbate corresponded with decreases in GSH levels, pro-survival signaling (pNF-κB, pERK1/2), and in expression of X-linked inhibitor of apoptosis protein (XIAP), the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and Annexin V staining, administration of a pan-caspase inhibitor, QVD-OPh, did not reverse the observed cytotoxicity. MnP + ascorbate treated cells showed nuclear translocation of apoptosis inducing factor (AIF), suggesting the possibility of a mechanism of caspase-independent cell death. Pharmacological ascorbate has already shown promise in recently completed Phase I Clinical Trials, where its oxidation and subsequent peroxide formation was catalyzed by endogenous metalloproteins. The catalysis of ascorbate oxidation by an optimized metal-based catalyst (such as Mn porphyrin) carries a large therapeutic potential as a sole anticancer agent or in combination with other modalities such as radio- and chemo- therapy.

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Section: Discussionsupporting

confidence: 74%

Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death

Evans

Tovmasyan

Batinić‐Haberle

et al. 2014

Free Radical Biology and Medicine

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“…Once within the organelle, Bax participates in the opening of the mtPTP, which is promptly followed by release of proapoptotic AIF and cytochrome c into the cytosol (12, 28, 32, 33, 40). Upon release, AIF and cytochrome c proceed to induce DNA fragmentation either directly or via a caspase cascade (12,28,32,33,40). Accordingly, AIF and cytochrome c localization to the cytosol was evident with H 2 O 2 treatment.…”

Section: Discussionmentioning

confidence: 99%

Effects of endurance training on apoptotic susceptibility in striated muscle

Vainshtein

Kazak

Hood

2011

Journal of Applied Physiology

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An increase in the production of reactive oxygen species occurs with muscle disuse, ischemic cardiomyopathy, and conditions that arise with senescence. The resulting oxidative stress is associated with apoptosis-related myopathies. Recent research has suggested that chronic exercise is protective against mitochondrially mediated programmed cell death. To further investigate this, we compared soleus (Sol) and cardiac muscles of voluntary wheel-trained (T; 10 wk) and untrained (C) animals. Training produced a 52% increase in muscle cytochrome c oxidase (COX) activity. Sol and left ventricle (LV) strips were isolated and incubated in vitro with H2O2 for 4 h. Strips were then fractionated into cytosolic and mitochondrial fractions. Whole muscle apoptosis-inducing factor (AIF) and Bax/Bcl-2 levels were reduced in both the Sol and LV from T animals. H2O2 treatment induced increases in JNK phosphorylation, cofilin-2 localization to the mitochondria, as well as cytosolic AIF in both Sol and LV of T and C animals, respectively. Mitochondrial Bax and cytosolic cytochrome c were augmented under oxidative stress in the LV only. The H2O2-induced increases in P-JNK, mitochondrial Bax, and cytosolic AIF were ablated in the LV of T animals. These data suggest that short-term oxidative stress can induce apoptotic signaling in striated muscles in vitro. In addition, training can attenuate oxidative stress-induced apoptotic signaling in a tissue-specific manner, with an effect that is most prominent in cardiac muscle.

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“…Accordingly, treatment of Aif-depleted human cells (Hep3B and HeLa cell lines) with antioxidants ( N -acetyl-cysteine or MitoQ) failed to restore complex I integrity [29] , suggesting primary loss of complex I, which might increase superoxide leakage. Conversely, the (pro-oxidant) superoxide-generating NADH oxidase activity of Aif may be required for normal muscle regeneration [30] . Taken in concert, the data suggest that any antioxidant effects of Aif may be confined to the close vicinity of complex I, so that Aif acts as a complex I maintenance protein.…”

Section: Discussionmentioning

confidence: 99%

“…Antioxidant enzyme induction in muscle-specific Aif knockout mutants [24] and in skeletal muscle from our Hq mice appears to be tissue-specific and may reflect either an additional role for Aif in muscle or a tissue-specific consequence of RCCI. Although the role for Aif remains debated [26] , [29] , [30] , the effects of Aif deficiency are similar to those of deficiency in any complex I assembly/maintenance factor. NDUFS4 knockout mice exhibit severe RCCI with features similar to those of Hq mice (growth retardation, blindness, ataxia, and baldness) but greater disease severity leading to death at 7 weeks of age after only 2 weeks with symptoms.…”

Section: Discussionmentioning

confidence: 99%

The Variability of the Harlequin Mouse Phenotype Resembles that of Human Mitochondrial-Complex I-Deficiency Syndromes

et al. 2008

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BackgroundDespite the considerable progress made in understanding the molecular bases of mitochondrial diseases, no effective treatments have been developed to date. Faithful animal models would be extremely helpful for designing such treatments. We showed previously that the Harlequin mouse phenotype was due to a specific mitochondrial complex I deficiency resulting from the loss of the Apoptosis Inducing Factor (Aif) protein.Methodology/Principal FindingsHere, we conducted a detailed evaluation of the Harlequin mouse phenotype, including the biochemical abnormalities in various tissues. We observed highly variable disease expression considering both severity and time course progression. In each tissue, abnormalities correlated with the residual amount of the respiratory chain complex I 20 kDa subunit, rather than with residual Aif protein. Antioxidant enzyme activities were normal except in skeletal muscle, where they were moderately elevated.Conclusions/SignificanceThus, the Harlequin mouse phenotype appears to result from mitochondrial respiratory chain complex I deficiency. Its features resemble those of human complex I deficiency syndromes. The Harlequin mouse holds promise as a model for developing treatments for complex I deficiency syndromes.

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Mitochondrial AIF protein involved in skeletal muscle regeneration

Cited by 4 publications

References 18 publications

Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death

Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death

Effects of endurance training on apoptotic susceptibility in striated muscle

The Variability of the Harlequin Mouse Phenotype Resembles that of Human Mitochondrial-Complex I-Deficiency Syndromes

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