Inhibition of mitochondrial protein synthesis results in increased endothelial cell susceptibility to nitric oxide-induced apoptosis

Ramachandran, Anup; Moellering, Douglas R.; Ceaser, Erin K.; Shiva, Sruti; Xu, Jun; Darley‐Usmar, Victor

doi:10.1073/pnas.102019899

Cited by 58 publications

(41 citation statements)

References 41 publications

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“…We found that CAP did not significantly affect ATP levels in the neurons (Fig. 5C), consistent with the lack of effect of CAP treatment for up to 55 h on ATP levels in other cell types in culture (37). To examine the effect of CAP on mitochondrial membrane potential (⌬ M ), we monitored the dequenching of tetramethylrhodamine methyl ester fluorescence evoked by bath applying the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (38) in individual neurons from CAP-treated or control cultures.…”

Section: Loss Of Nd2 In Neurons Prevents the Regulation Of Nmda Receptorsupporting

confidence: 69%

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

Gingrich

Pelkey

Fam

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

117

115

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Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein–protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling

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Section: Loss Of Nd2 In Neurons Prevents the Regulation Of Nmda Receptorsupporting

confidence: 69%

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

Gingrich

Pelkey

Fam

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

117

115

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“…mtDNA is responsible for the synthesis of 13 subunits of mitochondrial electron transport chain (Anderson et al, 1981). Because turnover of mitochondrial proteins occurs independently (Ramachandran et al, 2002), imbalance and/or impairment of the electron transport system caused by mtDNA injury may facilitate leakage of electrons to generate the superoxide radical (Han et al, 2001). Although rotenone (50 M) and antimycin (50 M) instantaneously increase mitochondrial ROS (data not shown), its generation induced by the agents interacting with DNA increased fairly slowly (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Hara¹,

Kasahara²,

Takahashi³

et al. 2011

J Pharmacol Exp Ther

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Although chemotherapy is an important method for the treatment of patients with cancer, its efficacy is limited because of different sensitivities of tumor cells to anticancer agents and/or side effects on normal tissues. The present work demonstrates that mitochondria play a crucial role in the apoptosis of cancer cells induced by anticancer agents that interact with DNA but not with the cytoskeleton. Agents that interact with DNA selectively enhanced generation of reactive oxygen species (ROS) in mitochondria, released cytochrome c, and activated caspase-9 and caspase-3 to induce apoptosis of mesothelioma H2052 cells but not their 0 cells, which lack mitochondrial DNA (mtDNA). The sensitivity of a variety of cells to the agents showed positive correlation with the amounts of their mitochondria. In contrast, agents that selectively affect the cytoskeleton activated caspase-8 and caspase-3 and equally induced apoptosis of both H2052 and their 0 cells by a mitochondria-independent mechanism. The results suggest that mtDNA is a potential target for the anticancer agents that interact with DNA to induce ROS-dependent apoptosis of cancer cells, whereas agents that affect the cytoskeleton induce cell death by a mitochondria-and ROS-independent mechanism. The present observation is important for the selection of medicine for chemotherapy of patients with cancer.

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“…2A-C). Both TNF-␣ (a cytokine shown to reduce mitochondrial biogenesis and increase susceptibility to mitochondrial injury [18,19]) and chloramphenicol (a specific inhibitor of mitochondrial protein synthesis [20]) reduced adiponectin synthesis and mtDNA content (Fig. 2F and G).…”

Section: Resultsmentioning

confidence: 99%

“…The db/db mice were treated for 4 weeks with 20 (13). Oxygen comsumption in epididymal adipose tissue was measured using a 782 single-dual-channel oxygen meter (Strathkelvin Instruments, Glasgow, U.K.).…”

Section: Methodsmentioning

confidence: 99%

Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes

et al. 2007

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OBJECTIVE-Adiponectin is an important adipocytokine that improves insulin action and reduces atherosclerotic processes. The plasma adiponectin level is paradoxically reduced in obese individuals, but the underlying mechanism is unknown. This study was undertaken to test the hypothesis that mitochondrial function is linked to adiponectin synthesis in adipocytes.RESEARCH DESIGN AND METHODS-We examined the effects of rosiglitazone and the measures that increase or decrease mitochondrial function on adiponectin synthesis. We also examined the molecular mechanism by which changes in mitochondrial function affect adiponectin synthesis.RESULTS-Adiponectin expression and mitochondrial content in adipose tissue were reduced in obese db/db mice, and these changes were reversed by the administration of rosiglitazone. In cultured adipocytes, induction of increased mitochondrial biogenesis (via adenoviral overexpression of nuclear respiratory factor-1) increased adiponectin synthesis, whereas impairment in mitochondrial function decreased it. Impaired mitochondrial function increased endoplasmic reticulum (ER) stress, and agents causing mitochondrial or ER stress reduced adiponectin transcription via activation of c-Jun NH 2 -terminal kinase (JNK) and consequent induction of activating transcription factor (ATF)3. Increased mitochondrial biogenesis reversed all of these changes.CONCLUSIONS-Mitochondrial function is linked to adiponectin synthesis in adipocytes, and mitochondrial dysfunction in adipose tissue may explain decreased plasma adiponectin levels in obesity. Impaired mitochondrial function activates a series of mechanisms involving ER stress, JNK, and ATF3 to decrease adiponectin synthesis. Diabetes

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Inhibition of mitochondrial protein synthesis results in increased endothelial cell susceptibility to nitric oxide-induced apoptosis

Cited by 58 publications

References 41 publications

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes

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