Mitochondrial stress signaling in disease and aging (474.3)

Myocardial infarction is the single most prevalent cause of morbidity and mortality among adults. Excess generation of reactive oxygen species plays a major role in the cellular response to cardiac ischemia/reperfusion (I/R) injury. Accumulated evidence indicates that oxidative stress in mitochondria plays an important role in I/R injury, but how mitochondrial redox mechanisms are involved in cardiac dysfunction remains unclear. Manganese Superoxide Dismutase (MnSOD), an antioxidant enzyme that catalyzes the conversion of superoxide radicals (O 2 •-) in mitochondria. The absence of SOD2 (a gene that encodes MnSOD) is found to be embryonic lethal in animal models due to impairment of mitochondrial function, most noticeably in the heart. In our investigation, we found MnSOD mimetic, MnTnBuOE-2-PyP 5+ distributed 3-fold more in mitochondria than in cytosol. The exceptional ability of MnTnBuOE-2-PyP 5+ to dismute O 2 •- parallels its ability to reduce ONOO– and CO3–. Based on our initial results, we have generated mice that specifically lack MnSOD in cardiomyocytes (Mhy6-SOD2 Δ ). These mice showed early mortality ~6 months due to cardiac mitochondrial dysfunction. FACS analyses using Mito-Tracker Green indicated that the mass of mitochondria per cell was slightly decreased in the Mhy6-SOD2 Δ to the wild type. We then examined oxidative phosphorylation levels in Mhy6-SOD2 Δ v.s. wild type using a Seahorse XF analyzer. The rate of oxygen consumption per cells was significantly lower in Mhy6-SOD2 Δ cardiomyocytes than that in wild type. The most noticeable difference in the O 2 consumption was found in the presence of FCCP (H+ ionophore/uncoupler). 4-hydroxy-2-nonenal (HNE) adduction of mitochondrial apoptosis-inducing factor (AIFm2) inactivates the NADH oxidoreductase activity of AIFm2 and facilitates its translocation from mitochondria. His 174 on AIFm2 is the critical target of HNE adduction that triggers this functional switch. HNE adduction and translocation of AIFm2 from mitochondria following I/R injury are attenuated by superoxide dismutase mimetics. These results identify a previously unrecognized role of the MnSOD-HNE-AIFm2 axis, with important consequences for mitochondrial stress signaling, especially in cardiac I/R injury.

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African Swine Fever Virus Inhibits Induction of the Stress-Induced Proapoptotic Transcription Factor CHOP/GADD153

Journal of Virology ◽

10.1128/jvi.78.19.10825-10828.2004 ◽

2004 ◽

Vol 78 (19) ◽

pp. 10825-10828 ◽

Cited By ~ 31

Author(s):

Christopher L. Netherton ◽

James C. Parsley ◽

Thomas Wileman

Keyword(s):

Transcription Factor ◽

African Swine Fever Virus ◽

Stress Protein ◽

African Swine Fever ◽

Fever Virus ◽

Stress Signaling ◽

Mitochondrial Stress ◽

Cytoplasmic Face ◽

Infected Cells ◽

A Site

ABSTRACT Stress signaling from mitochondria and the endoplasmic reticulum (ER) leads to the induction of the proapoptotic transcription factor CHOP/GADD153. Many viruses use the ER as a site of replication and/or envelopment, and this activity can lead to the activation of ER stress and apoptosis. African swine fever virus (ASFV) is assembled on the cytoplasmic face of the ER and ultimately enveloped by ER membrane cisternae. The virus also recruits mitochondria to sites of viral replication and induces the mitochondrial stress protein hsp60. Here we studied the effects of ASFV on the induction of CHOP/GADD153 in infected cells. Interestingly, unlike other ER-tropic viruses, ASFV did not activate CHOP and was able to inhibit the induction of CHOP/GADD153 by a number of exogenous stimuli.

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Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation

The Journal of Cell Biology ◽

10.1083/jcb.201604065 ◽

2017 ◽

Vol 216 (3) ◽

pp. 815-834 ◽

Cited By ~ 18

Author(s):

Taiichi Tsuyama ◽

Asako Tsubouchi ◽

Tadao Usui ◽

Hiromi Imamura ◽

Tadashi Uemura

Keyword(s):

Drosophila Melanogaster ◽

Mitochondrial Dysfunction ◽

Stress Signaling ◽

Dependent Manner ◽

Mitochondrial Stress ◽

Translation Repression ◽

Eif2α Phosphorylation ◽

Genetic Perturbations ◽

Class Iv

Mitochondria are key contributors to the etiology of diseases associated with neuromuscular defects or neurodegeneration. How changes in cellular metabolism specifically impact neuronal intracellular processes and cause neuropathological events is still unclear. We here dissect the molecular mechanism by which mitochondrial dysfunction induced by Prel aberrant function mediates selective dendritic loss in Drosophila melanogaster class IV dendritic arborization neurons. Using in vivo ATP imaging, we found that neuronal cellular ATP levels during development are not correlated with the progression of dendritic loss. We searched for mitochondrial stress signaling pathways that induce dendritic loss and found that mitochondrial dysfunction is associated with increased eIF2α phosphorylation, which is sufficient to induce dendritic pathology in class IV arborization neurons. We also observed that eIF2α phosphorylation mediates dendritic loss when mitochondrial dysfunction results from other genetic perturbations. Furthermore, mitochondrial dysfunction induces translation repression in class IV neurons in an eIF2α phosphorylation-dependent manner, suggesting that differential translation attenuation among neuron subtypes is a determinant of preferential vulnerability.

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