Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Novgorodov, Sergei A.; Voltin, Joshua; Gooz, Monika; Li, Li; Lemasters, John J.; Gudz, Tatyana I.

doi:10.1194/jlr.m080374

Cited by 69 publications

(66 citation statements)

References 85 publications

(122 reference statements)

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“…We suggest that cooperative cytotoxicity be considered among mechanisms of inter-species communication, providing enhanced ability to damage host tissue, increase inflammation, and introduce specific metabolic products associated with harm to humans. For example, ceramide (exposed on target cell membranes when sphingomyelin is hydrolyzed) is associated with an increasing range of physiological harm, including to mitochondrial function [16], and is recognized in the pathogenesis of Parkinsonism [17]. Oxidized sterols, a product of the sequential action of phospholipase and cholesterol oxidase have long been implicated in complex cardiovascular pathology [18].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Cytotoxins: A New Look at an Old Observation of Bacterial Crosstalk

Linder¹,

McIntyre²

2019

J Bacteriol Parasitol

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Cooperative (or synergistic) hemolysis, the ability of two bacterial species to jointly lyse erythrocytes, has long been recognized as a helpful tool in the identification of common pathogens (i.e. the CAMP reaction between Streptococcus agalactiae and Staphylococcus aureus). However, to examine these biological partnerships separately from their use in the diagnostic lab provides new perspectives on toxicity to host tissue during infections and in health. Many examples of such pairings exist, and typically reflect the sequential action of a phospholipase (e.g., PLC from Staphylococcus aureus or Clostridium perfringens), followed by a second bacterial toxin acting on the altered membrane, e.g. the CAMP protein of group B streptococci, or the cholesterol oxidase of Rhodococcus equi. Commonly occurring cooperative cytotoxic partnerships are reviewed, along with their biochemical mechanisms of action. Newly reported is the ability of hemolytic collaborations to accommodate a midcourse change in conditions of oxygenation. Thus, erythrocytes altered by PLC of C. perfringens grown anaerobically, are lysed following exposure to the strict aerobe R. equi, in air.Why does this matter? Microbial communities on tissue (i.e. the microbiome) are increasingly understood to impact the health of hosts. Pathogenesis, especially in anaerobic infections, often reflects the combined actions of microbial pathogens, commensal (resident) microorganisms, and metabolites from the host. Products of some cooperative reactions (i.e., ceramide and oxysterol) are directly toxic, e.g., to the immune system. Host environments include a range of oxygenation not intuitively evident, i.e., extreme anaerobiosis in the mouth, creating ideal conditions for cooperative cytotoxicity to occur in vivo. To appreciate the impact of common hydrolytic enzymes and other proteins from diverse sources deepens our understanding of the host and its complex microbial community. activity of Corynebacterium pseudotuberculosis (Corynebacterium ovis) and Corynebacterium ulcerans, a distinctive marker within the genus Corynebacterium. J Clin Microbiol. 1981;13(2):335-343. Linder R, et al.

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Section: Discussionmentioning

confidence: 99%

Cooperative Cytotoxins: A New Look at an Old Observation of Bacterial Crosstalk

Linder¹,

McIntyre²

2019

J Bacteriol Parasitol

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“…Another major pathway of sphingolipid metabolism starts with SM hydrolysis and is catalyzed by a sphingomyelinase family enzymes, ASM and NSM, yielding phosphorylcholine and ceramide (47). Hydrophobic ceramide is further hydrolyzed by ceramidase to form more hydrophilic sphingosine, which could leave the intracellular compartment, where it is generated to reach mitochondria (21,23,24). ASM is encoded by the Smpd1 gene and translated into 629 amino acid proprotein, which, because of differential modification and trafficking processes, gives rise to two distinct isoforms, lysosomal and secretory ASM (48).…”

Section: Tbi Triggered Asm Activation Via Posttranscriptional Mechanismsmentioning

confidence: 99%

“…It has been shown that a partial suppression of COX activity by cyanide increases mitochondrial ROS formation (53). Moreover, sphingosine-mediated modest inhibition of COX activity enhanced mitochondrial ROS emission in situ (24,52), which might contribute to oxidative stress, causing an imbalance between oxidant and antioxidant agents in the injured brain (54). Enhanced production of ROS could cause oxidative/nitrosative stress, leading to damage in lipids, proteins, and nucleic acids, known to occur in TBI (55).…”

Section: Tbi-induced Mitochondrial Dysfunction Is Rescued In Asm-defimentioning

confidence: 99%

“…Transfer of ceramide between intracellular compartments requires either the vesicular transport pathway (20) or nonvesicular mechanisms, including a transfer protein, ceramide transfer protein (21,22). In contrast, it has been shown that sphingosine can leave the lysosomal compartment and impact mitochondria (23,24). We hypothesized that TBI could trigger an activation of ASM/acid ceramidase-dependent generation of lysosomal sphingosine, which could reach mitochondria, increasing mitochondrial sphingosine levels and mitochondrial dysfunction, fostering secondary brain injury.…”

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confidence: 98%

“…In apoptosis induced by TNF-, IFN-, and radiation (21,27), ASM activation led to formation of ceramide-enriched membrane platforms that are central for apoptotic signal transduction (28,29). ASM/acid ceramidase-dependent mitochondrial sphingosine accumulation was shown to perturb mitochondrial function, which results in regulated necrotic cell death, ferroptosis (24). Of note, an inhibition of ASM activity mediates the effects of antidepressant drugs (30,31) and diminishes symptoms associated with AD (32).…”

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confidence: 99%

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Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

Novgorodov

Voltin

Wang

et al. 2019

Journal of Lipid Research

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Traumatic brain injury (TBI) is one of the leading causes of disability worldwide and a prominent risk factor for neurodegenerative diseases. The expansion of nervous tissue damage after the initial trauma involves a multifactorial cascade of events including excitotoxicity, oxidative stress, inflammation and deregulation of sphingolipid metabolism that further mitochondrial dysfunction and secondary brain damage. Our studies establish a fundamental role of acid sphingomyelinase (ASM) in the multi‐faceted mechanisms governing secondary brain injury after TBI. The data indicate that TBI‐triggered activation of ASM and upregulation of mitochondrial sphingosine resulted in mitochondrial respiratory chain malfunction leading to an enhanced assembly and activity of the NLRP3 inflammasome, a pivotal factor promoting the neuroinflammatory response to brain injury. The results of our studies provide further support for the emerging role of ASM in repressing the cell maintenance and quality control mechanism, autophagy, which is essential for the neural cell survival after the injury. Thus, knocking down ASM rescued mitochondrial defect, augmented the autophagic flux, downregulated the neuroinflammation and improved the brain function recovery after TBI. Importantly, ASM is involved in the initial stages of progression of astrogliosis, a brain defense mechanism wherein activated astrocytes minimize spread of the neuroinflammation and further tissue repair and regeneration in response to TBI. Our novel findings reveal that ASM, a critical player promoting secondary brain injury and neuroinflammation is uniquely positioned to be a promising target for the development of effective pharmacological treatment of patients with TBI. Support or Funding Information Supported by NIH grant R01NS083544 (TIG) and VA Merit Award I01BX002991 (TIG). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

Han

Jiang

et al. 2020

Journal Cellular Physiology

164

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Ferroptosis, an autophagy‐dependent cell death, is characterized by lipid peroxidation and iron accumulation, closely associated with pathogenesis of gestational diabetes mellitus (GDM). Sirtuin 3 (SIRT3) has positive regulation on phosphorylation of activated protein kinase (AMPK), related to maintenance of cellular redox homeostasis. However, whether SIRT3 can confer autophagy by activating the AMPK‐mTOR pathway and consequently promote induction of ferroptosis is unknown. We used human trophoblastic cell line HTR8/SVneo and porcine trophoblastic cell line pTr2 to deterimine the mechanism of SIRT3 on autophagy and ferroptosis. The expression of SIRT3 protein was significantly elevated in trophoblastic cells exposed to high concentrations of glucose and ferroptosis‐inducing compounds. Increased SIRT3 expression contributed to classical ferroptotic events and autophagy activation, whereas SIRT3 silencing led to resistance against both ferroptosis and autophagy. In addition, autophagy inhibition impaired SIRT3‐enhanced ferroptosis. On the contrary, autophagy induction had a synergistic effect with SIRT3. Based on mechanistic investigations, SIRT3 depletion inhibited activation of the AMPK‐mTOR pathway and enhanced glutathione peroxidase 4 (GPX4) level, thereby suppressing autophagy and ferroptosis. Furthermore, depletion of AMPK blocked induction of ferroptosis in trophoblasts. We concluded that upregulated SIRT3‐enhanced autophagy activation by promoting AMPK‐mTOR pathway and decreasing GPX4 level to induce ferroptosis in trophoblastic cells. SIRT3 deficiency was resistant to high glucose‐ and erastin‐induced autophagy‐dependent ferroptosis and is, therefore, a potential therapeutic approach for treating GDM.

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Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Cited by 69 publications

References 85 publications

Cooperative Cytotoxins: A New Look at an Old Observation of Bacterial Crosstalk

Cooperative Cytotoxins: A New Look at an Old Observation of Bacterial Crosstalk

Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

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