Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Sundaram, Kumaran; Mather, Andrew R.; Marimuthu, Subathra; Shah, Parag P.; Snider, Ashley J.; Obeid, Lina M.; Hannun, Yusuf A.; Beverly, Levi J.; Siskind, Leah J.

doi:10.1042/bj20150586

Cited by 35 publications

(36 citation statements)

References 77 publications

(78 reference statements)

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“…The observed Asah2 mRNA reduction would serve to maintain ceramide and minimize the production of sphingosine [117], so it does not explain the sphingosine accumulation. A deficiency of nCDase protects from ER stress and from nutrient-deprivation-induced necroptosis via autophagy, while decreasing the formation of S1P at the plasma membrane [118][119][120], so this enzyme downregulation is in good agreement with the low S1P levels observed in the KIN cerebellum and may play a compensatory role.…”

Section: Utilization Of Ceramide In Atxn2-cag100-kin Mouse Tissuessupporting

confidence: 58%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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Section: Utilization Of Ceramide In Atxn2-cag100-kin Mouse Tissuessupporting

confidence: 58%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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“…All experiments were repeated at least twice with similar results; error bars represent SD of a single experiment. ***P , 0.001. empirically (and glucose as osmotic controls) to decrease HT-22 cell viability (39). Cell counts were not altered, even in the presence of 2-deoxyglucose (Supplemental Fig.…”

Section: Hsp27 Mutant Increases Autophagic Flux But Not Cellular Prolmentioning

confidence: 93%

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

et al. 2018

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Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide. Given that Hsp27 is a chaperone protein, we examined its role in regulating ceramide synthases (CerSs), an enzyme family responsible for catalyzing generation of the sphingolipid ceramide. We determined that CerSs colocalized with Hsp27, and upon the presence of S135F mutants, CerS1 lost its colocalization with mitochondria suggesting that decreased mitochondrial ceramides result from reduced mitochondrial CerS localization rather than decreased CerS activity. Mitochondria in mutant cells appeared larger with increased interconnectivity. Furthermore, mutant cell lines demonstrated decreased mitochondrial respiratory function and increased autophagic flux. Mitochondrial structural and functional changes were recapitulated by blocking ceramide generation pharmacologically. These results suggest that mutant Hsp27 decreases mitochondrial ceramide levels, producing structural and functional changes in mitochondria leading to neuronal degeneration.-Schwartz, N. U., Linzer, R. W., Truman, J.-P., Gurevich, M., Hannun, Y. A., Senkal, C. E., Obeid, L. M. Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F.

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“…Using a model of glycolysis inhibition via 2-deoxyglucose (2DG) and mitochondrial electron transport via antimycin A, Sundaram et al showed that loss of NC protected cells from nutrient deprivation-induced necroptosis via autophagy and clearance of damaged mitochondria (Sundaram et al, 2016). …”

Section: Neutral Ceramidase (Asah2 Asah2b Asah2c)mentioning

confidence: 99%

Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant

Sakamoto

Mao

et al. 2017

Advances in Biological Regulation

194

146

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Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P)(Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis. Ceramidases have the important role of cleaving fatty acid from ceramide and producing sphingosine, thereby controlling the interconversion of these two lipids. Thus far, five human ceramidases encoded by five different genes have been identified: acid ceramidase (AC), neutral ceramidase (NC), alkaline ceramidase 1 (ACER1), alkaline ceramidase 2 (ACER2), and alkaline ceramidase 3 (ACER3). These ceramidases are classified according to their optimal pH for catalytic activity. AC, which is localized to the lysosomal compartment, has been associated with Farber’s disease and is involved in the regulation of cell viability. Neutral ceramidase, which is localized to the plasma membrane and primarily expressed in the small intestine and colon, is involved in digestion, and has been implicated in colon carcinogenesis. ACER1 which can be found in the endoplasmic reticulum and is highly expressed in the skin, plays an important role in keratinocyte differentiation. ACER2, localized to the Golgi complex and highly expressed in the placenta, is involved in programed cell death in response to DNA damage. ACER3, also localized to the endoplasmic reticulum and the Golgi complex, is ubiquitously expressed, and is involved in motor coordination-associated Purkinje cell degeneration. This review seeks to consolidate the current knowledge regarding these key cellular players..

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Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Cited by 35 publications

References 77 publications

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

Ceramidases, roles in sphingolipid metabolism and in health and disease

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