Endoplasmic Reticulum-Targeted Bcl-2 Inhibitable Mitochondrial Fragmentation Initiates ER Stress-Induced Cell Death

Bhavya, B. C.; Indira, Deepa; Seervi, Mahendra; Joseph, Jeena; Sobhan, Praveen K.; Mathew, Krupa Ann; Varghese, Saneesh; Santhoshkumar, T.R.

doi:10.1007/978-1-4614-3381-1_7

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…44 The mitochondrial Ca 2+ overload generated leads to the depolarization of the inner membrane, the release of cytochrome c release and the activation of caspases. 45 In line with the reported occurrence of mitochondrial fission during ER stress [46][47][48] and the role of Drp1 in ER stress-induced apoptosis of pancreatic β-cells, 49 we found that PKA activation led to Drp1 inhibition, as monitored by Drp1 phosphorylation. Moreover, we demonstrated that PKA activation and Drp1 inhibition protected cells from apoptotosis induced by Tu but not by TNF or Eto, thereby identifying a direct mechanistic link for the protective effect of PKA activation in cells undergoing ER stress.…”

Section: Discussionsupporting

confidence: 85%

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

et al. 2016

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The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis-or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear. We performed a siRNA-based screen to identify new regulators of ER stress-induced death and found that repression of the Carney complex-associated protein PRKAR1A specifically protected the cells from ER stress-induced apoptosis, and not from apoptosis induced by etoposide or TNF. We demonstrate that the protection results from PKA activation and associate it, at least in part, with the phosphorylation-mediated inhibition of the PKA substrate Drp1 (dynamin-related protein 1). Our results therefore provide new information on the complex regulation of cellular death under ER stress conditions and bring new insights on the conditions that regulate the pro-versus anti-death functions of PKA.

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Section: Discussionsupporting

confidence: 85%

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

et al. 2016

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“…Much more is known about the morphologic changes of mitochondria during an ER stress that induces apoptosis even if the timing of certain remodelling events remains controversial. It is also unclear whether these morphological changes are necessary early events required for the release of pro‐apoptotic factors or are simply downstream effects (Breckenridge et al, 2003; Hom et al, 2007; Bhavya et al, 2012). Several studies suggest that mitochondrial remodelling and fission observed in apoptosis are the cause of cytochrome c release and subsequent activation of cell death pathways (Yuan et al, 2007; Faccenda et al, 2013).…”

Section: Impact Of An Er Stress On Mitochondrial Morphology and Bioenmentioning

confidence: 99%

Functional and morphological impact of ER stress on mitochondria

Vannuvel

Renard

Raes

et al. 2013

Journal Cellular Physiology

137

132

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Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum (ER) and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and unfolded protein response (UPR) as well as mitochondria play major roles in apoptosis. However, while the effects of major ER stress on cell death have been largely studied and reviewed, it becomes more and more evident that cells might regularly deal with sublethal ER stress, a condition that does not necessarily lead to cell death but might affect the function/activity of other organelles such as mitochondria. In this review, we will particularly focus on these new, interesting and intriguing metabolic and morphological events that occur during the early adaptative phase of the ER stress, before the onset of cell death, and that remain largely unknown. Relevance and implication of these mitochondrial changes in response to ER stress conditions for human diseases such as type II diabetes and Alzheimer's disease will also be considered.

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“…During tunicamycin-and thapsigargin-induced ER stress, Bcl-2 was found to mediate the stability of the ER membrane and to be involved in ER stress-mediated apoptosis (8,9). HA14-1, a Bcl-2 inhibitor, significantly increased proteasome inhibitor bortezomib-induced cell death by increasing JNK-and caspase-4-mediated ER stress-induced apoptosis (10).…”

Section: Introductionmentioning

confidence: 99%

The BH3 mimetic S1 induces endoplasmic reticulum stress-associated apoptosis in cisplatin-resistant human ovarian cancer cells although it activates autophagy

Liu

Sun

et al. 2013

Oncology Reports

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Abstract. SKOV3/DDP human ovarian cancer cells have been shown to be resistant to cisplatin. Although the BH3 mimetic S1 induces cell death in several types of tumor cells, it is unclear whether it induces death in drug-resistant cells. Herein, we found that S1 induced endoplasmic reticulum (ER) stress-associated apoptosis in both SKOV3 and SKOV3/DDP cells. S1 activated autophagy at early time points in SKOV3/ DDP cells, and inhibition of autophagy increased ER stressassociated apoptosis. Collectively, our data indicate that autophagy plays a protective role, but it cannot protect against S1-induced cell death in cisplatin-resistant SKOV3/DDP cells.

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Endoplasmic Reticulum-Targeted Bcl-2 Inhibitable Mitochondrial Fragmentation Initiates ER Stress-Induced Cell Death

Cited by 3 publications

References 19 publications

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

Functional and morphological impact of ER stress on mitochondria

The BH3 mimetic S1 induces endoplasmic reticulum stress-associated apoptosis in cisplatin-resistant human ovarian cancer cells although it activates autophagy

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