Mitochondrial Aberrations in Mucolipidosis Type IV

Jennings, John J.; Zhu, Jian Hui; Rbaibi, Youssef; Luo, Xiang; Chu, Charleen T.; Kiselyov, Kirill

doi:10.1074/jbc.m607982200

Cited by 137 publications

(133 citation statements)

References 70 publications

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“…Similar changes were observed in fibroblasts from patients with mucolipidosis type II and III and neuronal ceroid lipofuscinosis 2 (CLN2). 54 In GM1-gangliosidosis, the storage material accumulates not only in lysosomes but also in the mitochondria-associated ER membranes, where it alters the activity of the phosphorylated Ca 2C releasing channel, IP3; this leads to mitochondrial Ca 2C overload, mitochondrial membrane permeabilization, and activation of apoptosis. 16 The mitochondrial abnormalities we observed in Pompe skeletal muscle do not exactly fit the patterns reported for LSDs.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 The impaired autophagosomal-lysosomal fusion is likely to affect autophagic degradation of mitochondria. Indeed, mitochondrial dysfunction has been reported in several LSDs: GM1-gangliosidosis 15, 16 and mucolipidosis II, III, and IV, 17,18 neuronal ceroid lipofuscinosis or Batten disease, 19 Gaucher disease, 20 and multiple sulfatase deficiency. 21 However, accumulation of anomalous mitochondria in these diseases is not simply a result of autophagic block, but rather a consequence of a particular mechanism, which is disease-and even tissue-specific.…”

Section: Introductionmentioning

confidence: 99%

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Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

et al. 2015

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“…As with most lysosomal storage diseases, the mechanisms of cell death in MLIV are unclear. We have previously suggested that lysosomal deficiencies in MLIV and, perhaps, other storage diseases, lead to autophagic deficits and buildup of effete mitochondria, which may expose cells to proapoptotic effects of cell stimulation with Ca 2ϩ mobilizing agonists (23). Autophagy deficits have been confirmed in MLIV and several other lysosomal storage models (18, 24 -28, 30).…”

Section: Mucolipidosis Type IV (Mliv) Is a Lysosomal Storage Diseasementioning

confidence: 94%

Loss of Lysosomal Ion Channel Transient Receptor Potential Channel Mucolipin-1 (TRPML1) Leads to Cathepsin B-dependent Apoptosis

Colletti

Miedel

Quinn

et al. 2012

Journal of Biological Chemistry

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Background: Mechanisms of cell death in mucolipidosis type IV, a lysosomal storage disease caused by mutations in gene coding for ion channel TRPML1, are unknown. Results: Acute TRPML1 knockdown increases apoptosis mediated by cytoplasmic cathepsin B (CatB) and Bax activity. Conclusion: TRPML1 loss results in Bax-and CatB-dependent apoptosis. Significance: This shows the first mechanistic link between TRPML1 loss, lysosomal deficiencies, and cell death.

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“…Consequently, high levels of chelatable Zn 2ϩ accrue in ethambutol-induced vacuoles, which induce lysosomal membrane permeabilization and retinal cell death (13). The association of chelatable Zn 2ϩ in neurodegeneration led us to study its potential role in mucolipidosis IV (MLIV), 3 a developmental disorder that results in large hyperacidic lysosomes, membranous vacuole formation, autophagic dysfunction, and mitochondrial fragmentation (15)(16)(17)(18). MLIV is an autosomal, recessive disease that generally results in brain and cognitive dysfunction, corneal clouding, and retinal cell degeneration leading to blindness, anemia, and achlorhydria (lack of gastric acid production in the stomach) (19).…”

mentioning

confidence: 99%

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

Eichelsdoerfer

Evans

Slaugenhaupt

et al. 2010

Journal of Biological Chemistry

102

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Chelatable zinc is important in brain function, and its homeostasis is maintained to prevent cytotoxic overload. However, certain pathologic events result in intracellular zinc accumulation in lysosomes and mitochondria. Abnormal lysosomes and mitochondria are common features of the human lysosomal storage disorder known as mucolipidosis IV (MLIV). MLIV is caused by the loss of TRPML1 ion channel function. MLIV cells develop large hyperacidic lysosomes, membranous vacuoles, mitochondrial fragmentation, and autophagic dysfunction. Here, we observed that RNA interference of mucolipin-1 gene (TRPML1) in HEK-293 cells mimics the MLIV cell phenotype consisting of large lysosomes and membranous vacuoles that accumulate chelatable zinc. To show that abnormal chelatable zinc levels are indeed correlated with MLIV pathology, we quantified its concentration in cultured MLIV patient fibroblast and control cells with a spectrofluorometer using N-(6-methoxy-8-quinolyl)-p-toluene sulfonamide fluorochrome. We found a significant increase of chelatable zinc levels in MLIV cells but not in control cells. Furthermore, we quantified various metal isotopes in whole brain tissue of TRPML1 ؊/؊ null mice and wild-type littermates using inductively coupled plasma mass spectrometry and observed that the zinc-66 isotope is markedly elevated in the brain of TRPML1 ؊/؊ mice when compared with controls. In conclusion, we show for the first time that the loss of TRPML1 function results in intracellular chelatable zinc dyshomeostasis. We propose that chelatable zinc accumulation in large lysosomes and membranous vacuoles may contribute to the pathogenesis of the disease and progressive cell degeneration in MLIV patients.Zinc (Zn 2ϩ ) is a redox-inert yet crucial trace element for virtually all organisms. Zn 2ϩ is second to iron in biological trace metal abundance and is known to play an important role in human brain function (1, 2). Some enzymes require Zn 2ϩ as co-factors, but many proteins use it for structural stability and thus are tightly bound (non-chelatable form) (3). A chelatable pool of Zn 2ϩ is present in cells, most notably in glutamatergic vesicles, and gets released at the neuronal synapse during normal and pathological states (4, 5). Because high levels of chelatable Zn 2ϩ or any trace metals produce cellular and mitochondrial toxicity (1, 6, 7), it is imperative that Zn 2ϩ homeostasis is actively maintained inside and outside of the cells. Certain pathological events such as epilepsy, cerebral stroke, and traumatic brain injury result in uncontrolled release and accumulation of chelatable Zn 2ϩ in neurons (1, 8) via voltage-gated or calcium-permeable ion channels (9). Furthermore, endosomes, autophagosomes, and lysosomes, which are critical organelles involved in the recycling and degradation of many proteins, are known compartments where chelatable Zn 2ϩ accumulates upon cellular perturbation (10 -12). Interestingly, chelatable Zn 2ϩ appears to mediate vacuolar formation in primary retinal cells exposed to ethambutol (an anti...

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Mitochondrial Aberrations in Mucolipidosis Type IV

Cited by 137 publications

References 70 publications

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

Loss of Lysosomal Ion Channel Transient Receptor Potential Channel Mucolipin-1 (TRPML1) Leads to Cathepsin B-dependent Apoptosis

Zinc Dyshomeostasis Is Linked with the Loss of Mucolipidosis IV-associated TRPML1 Ion Channel

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