Loss of Caspase-2-dependent Apoptosis Induces Autophagy after Mitochondrial Oxidative Stress in Primary Cultures of Young Adult Cortical Neurons.
Summary of "Loss of Caspase-2-dependent Apoptosis Induces Autophagy after Mitochondrial Oxidative Stress in Primary Cultures of Young Adult Cortical Neurons."
Mitochondrial dysfunctions have been associated with neuronal apoptosis and are characteristic of neurodegenerative conditions. Caspases play a central role in apoptosis; however, their involvement in mitochondrial dysfunction-induced neuronal apoptosis remains elusive. In the present report using rotenone, a complex I inhibitor that causes mitochondrial dysfunction, we determined the initiator caspase and its role in cell death in primary cultures of cortical neurons from young adult mice (1-2 months old). By pretreating the cells with a cell-permeable, biotinylated pan-caspase inhibitor that irreversibly binds to and traps the active caspase, we identified caspase-2 as an initiator caspase activated in rotenone-treated primary neurons. Loss of caspase-2 inhibited rotenone-induced apoptosis; however, these neurons underwent a delayed cell death by necrosis. We further found that caspase-2 acts upstream of mitochondria to mediate rotenone-induced apoptosis in neurons. The loss of caspase-2 significantly inhibited rotenone-induced activation of Bid and Bax and the release of cytochrome c and apoptosis inducing factor from mitochondria. Rotenone-induced downstream activation of caspase-3 and caspase-9 were also inhibited in the neurons lacking caspase-2. Autophagy was enhanced in caspase-2 knock-out neurons after rotenone treatment, and this response was important in prolonging neuronal survival. In summary, the present study identifies a novel function of caspase-2 in mitochondrial oxidative stress-induced apoptosis in neurons cultured from young adult mice.
Affiliation
From the Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
Journal Details
This article was published in the following journal.
Name: The Journal of biological chemistry
ISSN: 1083-351X
Pages: 8493-506
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21216964
- DOI: http://dx.doi.org/10.1074/jbc.M110.163824
Medical and Biotech [MESH] Definitions
X-linked Inhibitor Of Apoptosis Protein
An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.
Caspase 6
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
Caspase 7
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
Casp8 And Fadd-like Apoptosis Regulating Protein
An APOPTOSIS-regulating protein that is structurally related to CASPASE 8 and competes with CASPASE 8 for binding to FAS ASSOCIATED DEATH DOMAIN PROTEIN. Two forms of CASP8 and FADD-like apoptosis regulating protein exist, a long form containing a caspase-like enzymatically inactive domain and a short form which lacks the caspase-like domain.
Caspase 12
A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 9 is activated by pro-apoptotic factors that are released during cell stress and by CARD SIGNALING ADAPTOR PROTEINS. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.
PubMed Articles
SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-...
In this study, the anticancer effect of icariin, a natural flavonol glycoside, against human hepatoma SMMC-7721 cells and the underlying mechanisms were investigated. Icariin triggered the mitochondri...
Embelin induces apoptosis through down-regulation of XIAP in human leukemia cells.
The present study was undertaken to determine the molecular mechanisms by which embelin induces apoptosis in human leukemia cells. Embelin resulted in loss of cell viability and inhibition of prolifer...
The antitumor effects and molecular mechanism of NPC-16, a novel naphthalimide-polyamine conjugate, were evaluated in HepG2 cells and Bel-7402 cells. Apoptosis and necrosis were evaluated by Annexin V...
A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes.
Caspase 8 plays a dual role in the survival of T lymphocytes. Although active caspase 8 mediates apoptosis upon death receptor signaling, the loss of caspase 8 activity leads to receptor-interacting p...
Clinical Trials
Trial of MitoQ for Raised Liver Enzymes Due to Hepatitis C
A Phase 2, randomized, double-blind, parallel design trial of two doses of mitoquinone mesylate (MitoQ) and of placebo in patients with chronic Hepatitis C. MitoQ is a mitochondria-target...
Nucleoside reverse transcriptase inhibitors (NRTIs) are a class of anti-HIV drug that can be an important part of an HIV treatment regimen. Because anti-HIV therapy may have negative side...
An association between insulin resistance and mitochondrial dysfunction has been observed in aging, T2D, and in offspring of patients with T2D. It remains to be determined whether pharmac...
Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
Our central hypothesis is that oral CoQ10 is a safe and effective treatment for children with inborn errors of mitochondrial energy metabolism due to defects in specific respiratory chain...
Hydroxychloroquine + Carboplatin, Paclitaxel and Bevacizumb in Non-Small Cell Lung Cancer (NSCLC)
The purpose of this study is to examine the combination of one standard treatment for lung cancer plus an additional drug, hydroxychloroquine. The standard treatment for lung cancer being...
