Common and Uncommon Pathogenic Cascades in Lysosomal Storage Diseases

Vitner, Einat B.; Platt, Frances M.; Futerman, Anthony H.

doi:10.1074/jbc.r110.134452

Cited by 325 publications

(289 citation statements)

References 59 publications

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“…12 ROS proliferation is a cellular phenotype shared by csg2Δ cells and human sphingolipidoses, diseases in which sphingolipids build-up abnormally. 15 Significantly, our work highlights mitochondria and associated metabolic pathways as targets of lipid toxicity. Dysfunctional AMPK signaling has been linked to human metabolic disease (including those induced by lipid overload) and cancer.…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

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Sphingolipids are structural components of cell membranes that have signaling roles to regulate many activities, including mitochondrial function and cell death. Sphingolipid metabolism is integrated with numerous metabolic networks, and dysregulated sphingolipid metabolism is associated with disease. Here, we describe a monogenic yeast model for sphingolipid accumulation. A csg2Δ mutant cannot readily metabolize and accumulates the complex sphingolipid inositol phosphorylceramide (IPC). In these cells, aberrant activation of Ras GTPase is IPC-dependent, and accompanied by increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial mass. Survival or death of csg2Δ cells depends on nutritional status. Abnormal Ras activation in csg2Δ cells is associated with impaired Snf1/AMPK protein kinase, a key regulator of energy homeostasis. csg2Δ cells are rescued from ROS production and death by overexpression of mitochondrial catalase Cta1, abrogation of Ras hyperactivity or genetic activation of Snf1/AMPK. These results suggest that sphingolipid dysregulation compromises metabolic integrity via Ras and Snf1/AMPK pathways.Sphingolipids are critical structural molecules in cell membranes, forming membrane microdomains by associating with cholesterol and specific proteins.1 Sphingolipid metabolites are also important signaling molecules linked to multiple other metabolic pathways with kinases and phosphatases as regulatory targets.2,3 Sphingolipids have roles in numerous cell processes, including regulation of mitochondrial function, cell death and aging.2,4 Cellular sphingolipid homeostasis is maintained by control of synthesis, breakdown and interorganellar transport of sphingolipid metabolites.1 The importance of sphingolipids is underscored by several lysosomal storage disorders, including Tay Sachs, Gaucher and Nieman-Pick diseases, which are attributable to defective sphingolipid breakdown; similarly, a hereditary sensory neuropathy is caused by accumulation of abnormal sphingolipid metabolites.

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Section: Discussionmentioning

confidence: 99%

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

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“…Acidic lysosomal organelles mediate crucial biological processes such as degradation, catabolite export, and metabolism-sensing 5–7 , and defects to these processes can result in lysosomal storage diseases 8–10 . The lysosomal membrane is decorated with channels and transporters that regulate the lysosome’s ionic homeostasis and physiological functions 5,11,12 .…”

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confidence: 99%

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

Lee

Guo

Zeng

et al. 2017

Nature

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TMEM175 is a lysosomal K+ channel important for maintaining the lysosomal membrane potential and pH stability1. It contains two homologous copies of a six-transmembrane (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif2–4. Present in a subset of bacteria and archaea, the prokaryotic TMEM175 contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 from Chamaesiphon minutus, CmTMEM175, whose architecture represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swap. The highly conserved TM1 acts as the pore lining inner helix, creating an hour-glass shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the C-terminal half of TM1s form a bottle neck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter plays the central role in channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears distinct from that of the classical K+ channel family.

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“…These deficiencies result in the accumulation of macromolecules that are normally catabolized by lysosomal enzymes. Substrate accumulation in the lysosomes causes progressive damage and death to affected cells, tissues, and organs [5,6]. Clinically, LSDs are a highly diverse collection of diseases that have variable presentations and broad symptom spectra, with patients presenting from the prenatal period through adulthood.…”

Section: Introductionmentioning

confidence: 99%

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

Kishnani

Dickson

Muldowney

et al. 2016

Molecular Genetics and Metabolism

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Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction, Molecular Genetics and Metabolism (2015), doi: 10.1016/j.ymgme.2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The opinions presented herein are those of the authors and do not reflect the positions of all participants nor the institutions they represent. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

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Common and Uncommon Pathogenic Cascades in Lysosomal Storage Diseases

Cited by 325 publications

References 59 publications

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

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