SLP-2 is required for stress-induced mitochondrial hyperfusion

Tondera, Daniel; Grandemange, Stéphanie; Jourdain, Alexis A.; Karbowski, Mariusz; Mattenberger, Yves Benoît; Herzig, Sébastien; Cruz, Sandrine Da; Clerc, Pascaline; Raschke, Ines; Merkwirth, Carsten; Ehses, Sarah; Krause, Frank; Chan, David C.; Alexander, Christiane; Bauer, Christoph; Youle, Richard J.; Langer, Thomas; Martinou, Jean‐Claude

doi:10.1038/emboj.2009.89

Cited by 674 publications

(709 citation statements)

References 54 publications

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“…We found that high cisplatin concentrations induce SLP‐2 expression, which is in agreement with a previous study that suggested an anti‐apoptotic role of SLP‐2 in cells stressed with cycloheximide and UV irradiation 26. High cisplatin concentrations also increased the p‐MEK1/2 and p‐ERK1/2 levels, and decreased the ratio of Bax/Bcl‐2, cleaved caspase‐9/caspase‐9, cleaved caspase‐3/caspase‐3, and cleaved PARP/PARP in cervical cancer cells.…”

Section: Discussionsupporting

confidence: 93%

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Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Zhang

et al. 2018

Cancer Science

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Stomatin‐like protein 2 (STOML2 or SLP‐2) is an oncogenic anti‐apoptotic protein that is upregulated in several types of cancer, including cervical cancer. However, the mechanisms responsible for the SLP‐2 anti‐apoptotic function remain poorly understood. Here, we show that siRNA‐mediated SLP‐2 suppression decreases growth of human cervical cancer HELA and SIHA cells, and increases cisplatin‐induced apoptosis through activation of MEK/ERK signaling and suppression of the mitochondrial pathway. The inhibition of the mitochondrial pathway is mediated by increasing the mitochondrial Ca2+ concentration and mitochondrial membrane potential, thereby downregulating p‐MEK and p‐ERK levels, upregulating the Bax/Bcl‐2 ratio, increasing cytochrome C release from mitochondria into the cytosol, and upregulating levels of cleaved‐caspase 9, cleaved‐caspase 3, and cleaved poly ADP‐ribose polymerase (PARP). Overexpression of SLP‐2 using adenovirus‐STOML2 has the opposite effect: it upregulates p‐MEK and p‐ERK and downregulates the Bax/Bcl‐2 ratio and levels of cleaved‐caspase 9 to caspase 9, cleaved‐caspase 3 to caspase 3, and cleaved‐PARP to PARP in cisplatin‐treated cells. These data show that SLP‐2 inhibits cisplatin‐induced apoptosis by activating the MEK/ERK signaling and inhibiting the mitochondrial apoptosis pathway in cervical cancer cells.

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Section: Discussionsupporting

confidence: 93%

“…The protein is required for stress‐induced mitochondrial hyperfusion 26. Upregulation of SLP‐2 increases the mitochondrial membrane phospholipid cardiolipin, thus inducing mitochondrial biogenesis 27.…”

Section: Discussionmentioning

confidence: 99%

Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Zhang

et al. 2018

Cancer Science

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“…For electron microscopy, sample preparations and imaging was performed as described previously. 52 Isolation of mitochondria. Crude mitochondrial fractions were prepared by differential centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane (MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only proteins such as tBID, together with lipids of the MOM, are thought to play a key role in BAX and BAK activation. In particular, cardiolipin (CL) has been shown to stimulate tBID-induced BAX activation in vitro. However, it is still unclear whether this process also relies on CL in the cell, or whether it is more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To address this issue, we deleted both alleles of cardiolipin synthase in human HCT116 cells by homologous recombination, which resulted in a complete absence of CL. The CL-deficient cells were fully viable in glucose but displayed impaired oxidative phosphorylation and an inability to grow in galactose. Using these cells, we found that CL was not required for either tBID-induced BAX activation, or for apoptosis in response to treatment with TRAIL. Downregulation of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to mitochondria in apoptotic conditions. However, when both CL and MTCH2 were depleted, a significant reduction in tBID recruitment was observed, suggesting that in HCT116 cells, CL and MTCH2 can have redundant functions in this process.

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“…In agreement, lower H 2 O 2 doses induced mitochondrial hyperfusion associated to decreased Fis1 expression levels and augmented Mfn1 and Mfn2 . Probably hyperfusion represents a cellular defensive response, because elongated mitochondria display higher efficiency in ATP production that may aid the recovery from the oxidative insult (Mitra et al, 2009;Tondera et al, 2009). In addition, the onset of the mitochondrial permeability transition, process frequently followed by mitochondrial network fragmentation and apoptosis, was subject to redox regulation by oxidation of some components of the mitochondrial permeability transition pore (MPTP), such as critical thiols in the adenine nucleotide translocase and nitration of tyrosines of the voltage-dependent anion channel (for a review see Daiber, 2010).…”

Section: The Feedback Loop Between Ros Production and Mitochondrial Dmentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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SLP-2 is required for stress-induced mitochondrial hyperfusion

Cited by 674 publications

References 54 publications

Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

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