Adaptations of Energy Metabolism Associated with Increased Levels of Mitochondrial Cholesterol in Niemann-Pick Type C1-deficient Cells

Kennedy, Barry E.; Madreiter, Corina T.; Vishnu, Neelanjan; Malli, Roland; Graier, Wolfgang F.; Karten, Barbara

doi:10.1074/jbc.m114.559914

Cited by 67 publications

(73 citation statements)

References 56 publications

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“…This conclusion is further supported by our findings of downregulated expression of genes involved in the regulation of mitochondrial activity, including PGC1, cytochrome c, COX IV, and COX 8b, as well as the decreased expression of anti-oxidant genes such as GPX1, PRDX1, GSTA4, and SOD1 in NPC2-kd adipocytes. In accordance with the results from a recent study (18), our data clearly support the studies are needed to investigate the precise molecular mechanism for the role of NPC2 in the regulation of TLR signaling pathway activation.…”

Section: Discussionsupporting

confidence: 81%

“…In another study, increased accumulation of mitochondrial cholesterol and mitochondrial dysfunction was observed in NPC1-deficient Chinese hamster ovary cells (18). Although the accumulation of cholesterol in the late endosomes and lysosomes is believed to be the cause of NPC disease, its underlying mechanism for the NPC2 deficiency-caused pathologies, especially defective autophagy in adipocytes, has not been fully understood.…”

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confidence: 99%

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Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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Aging is a risk factor for the development of chronic metabolic diseases such as type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer. These aging-related diseases are known to be clustered together; aging-associated neurodegenerative disorders frequently coincide with type 2 diabetes, insulin resistance, obesity, and metabolic syndrome. This suggests that neurodegenerative disorders and type 2 diabetes share common genetic and metabolic features. Therefore, studying the role of the gene that contributes to neurodegenerative diseases in obesity and diabetes is of particular importance, as it may provide a clue for the pathological mechanism of the development of aging-related diseases. Intensive investigation on the underlying mechanisms of cellular aging has suggested that autophagy-lysosome and mitochondrial function plays an essential role in the regulation of cellular homeostasis and health (1). The autophagy-lysosome system is one of the main intracellular proteolytic systems that is responsible for the clearance of unwanted intracellular macromolecules and organelles (2). Cellular aging is associated with the disruption of this homeostatic mechanism, leading to the accumulation of oxidized/misfolded proteins, lipids, and damaged organelles (3). However, the genes and proteins that regulate autophagy-lysosomal activation and contribute to cellular aging remain largely unidentified.Autophagy is a highly regulated process that is inducible by nutrient deprivation and cellular stress. During nutrient deprivation, multiple signaling pathways cooperate to Abstract In this study, we investigated the role and mechanism of Niemann-Pick type C (NPC)2 in regulating lysosomal activity, mitophagy, and mitochondrial function in adipocytes. We found that knocking down NPC2 impaired lysosomal activity, as evidenced by the reduced mature cathepsin B, the increased accumulation of light chain 3 (LC3) and p62, and the decreased autophagic flux. In NPC2-knockdown (kd) adipocytes, the starvation-induced conversion of LC3-I to LC3-II was abolished. More interestingly, the majority of NPC2 was found in the mitochondrial fraction, and NPC2 deficiency led to impaired autophagic flux and decreased induction of LC3-II in the mitochondrial fraction during mitochondrial stress. Moreover, cellular respiration profiling revealed that NPC2-kd adipocytes had significantly decreased basal/maximal respiration and mitochondrial gene expression compared with scrambled cells, suggesting mitochondrial dysfunction. Additionally, we found that the mitochondrial recruitment of LC3-II induced by lipopolysaccharide (LPS), but not TNF, was blunted in NPC2-kd adipocytes. Most intriguingly, NPC2-kd selectively diminished LPS-induced NFB and ERK1/2 phosphorylation and the expression of pro-inflammatory genes, indicating that tolllike receptor signaling activation is impaired in the absence of NPC2. Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophag...

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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“…Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate. NPC1-deficient cells show increased lactate secretion, decreased glutamine-dependent mitochondrial respiration, and decreased ATP transport across mitochondrial membranes (21). Studies from NPC1-deficient mice cerebellum and cerebral cortex revealed an increase in lactate and a decrease in acetate/acetyl-CoA levels with disease progression as compared with wild-type (22).…”

Section: Corroboration Of Deps In Our Data Set With Previousmentioning

confidence: 99%

“…Energy Metabolism-Mitochondrial cholesterol accumulation can increase oxidative stress and in turn cause metabolic alterations in NPC1-deficient cells (21). Alterations in mitochondrial abundance, quality and electron transport chain have been suggested to affect energy homeostasis in the cerebellum of NPC1-deficient mice (22).…”

Section: Corroboration Of Deps In Our Data Set With Previousmentioning

confidence: 99%

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

Rauniyar¹,

Subramanian

Lavallée‐Adam³

et al. 2015

Molecular & Cellular Proteomics

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Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartments. Mutations in the NPC1 protein are implicated in 95% of patients with NPC disease. The most prevalent mutation is the missense mutation I1061T that occurs in ϳ15-20% of the disease alleles. In our study, an isobaric labeling-based quantitative analysis of proteome of NPC1I1061T primary fibroblasts when compared with wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. The relative expression level of a subset of differentially expressed proteins (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, and GAA) was independently and successfully substantiated by Western blotting. We observed that treating NPC1I1061T cells with four classes of seven different compounds that are potential NPC drugs increased the expression level of SOD2 and DHCR24. We have also shown an abnormal accumulation of glycogen in NPC1 I1061T fibroblasts possibly triggered by defective processing of lysosomal alpha-glucosidase. Our study provides a starting point for future more focused investigations to better understand the mechanisms by which the reported dysregulated proteins triggers the pathological cascade in NPC, and furthermore, their effect upon therapeutic interventions.

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“…Changes in cholesterol metabolism in the central nervous system (CNS) are linked to Alzheimer's disease, Parkinson disease, and Niemann-Pick C disease, and with mitochondrial dysfunction [188,189]. In Alzheimer's disease, -amyloid overproduction is associated with increased expression of Drp-1 and numbers of fragmented mitochondria, increased oxidative stress, and loss of ATP production, while familial Parkinson's disease has been linked to mutations in PINK1 and defective mitophagy [177].…”

Section: Pathophysiological Links Between Mitochondrial Function and mentioning

confidence: 99%

Mitochondrial regulation of macrophage cholesterol homeostasis

Graham

2015

Free Radical Biology and Medicine

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Adaptations of Energy Metabolism Associated with Increased Levels of Mitochondrial Cholesterol in Niemann-Pick Type C1-deficient Cells

Cited by 67 publications

References 56 publications

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

Mitochondrial regulation of macrophage cholesterol homeostasis

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