STARTing to understand MLN64 function in cholesterol transport

Rigotti, Attilio; Cohen, David E.; Zanlungo, Silvana

doi:10.1194/jlr.e008854

Cited by 17 publications

(15 citation statements)

References 25 publications

(20 reference statements)

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“…Moreover, HHpred analysis revealed a link between MOMTiP-5 and a beta barrel lipid binding protein MLN64 (e-value 0.0006) in H . sapiens which facilitates cholesterol transport to mitochondria [84]. These preliminary data support the existence of an outer mitosomal membrane-associated complex in G .…”

Section: Discussionsupporting

confidence: 63%

An Interactome-Centered Protein Discovery Approach Reveals Novel Components Involved in Mitosome Function and Homeostasis in Giardia lamblia

et al. 2016

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Protozoan parasites of the genus Giardia are highly prevalent globally, and infect a wide range of vertebrate hosts including humans, with proliferation and pathology restricted to the small intestine. This narrow ecological specialization entailed extensive structural and functional adaptations during host-parasite co-evolution. An example is the streamlined mitosomal proteome with iron-sulphur protein maturation as the only biochemical pathway clearly associated with this organelle. Here, we applied techniques in microscopy and protein biochemistry to investigate the mitosomal membrane proteome in association to mitosome homeostasis. Live cell imaging revealed a highly immobilized array of 30–40 physically distinct mitosome organelles in trophozoites. We provide direct evidence for the single giardial dynamin-related protein as a contributor to mitosomal morphogenesis and homeostasis. To overcome inherent limitations that have hitherto severely hampered the characterization of these unique organelles we applied a novel interaction-based proteome discovery strategy using forward and reverse protein co-immunoprecipitation. This allowed generation of organelle proteome data strictly in a protein-protein interaction context. We built an initial Tom40-centered outer membrane interactome by co-immunoprecipitation experiments, identifying small GTPases, factors with dual mitosome and endoplasmic reticulum (ER) distribution, as well as novel matrix proteins. Through iterative expansion of this protein-protein interaction network, we were able to i) significantly extend this interaction-based mitosomal proteome to include other membrane-associated proteins with possible roles in mitosome morphogenesis and connection to other subcellular compartments, and ii) identify novel matrix proteins which may shed light on mitosome-associated metabolic functions other than Fe-S cluster biogenesis. Functional analysis also revealed conceptual conservation of protein translocation despite the massive divergence and reduction of protein import machinery in Giardia mitosomes.

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Section: Discussionsupporting

confidence: 63%

An Interactome-Centered Protein Discovery Approach Reveals Novel Components Involved in Mitosome Function and Homeostasis in Giardia lamblia

et al. 2016

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“…In this study, we find that ATP levels are significantly increased in brains of both aged AD-Tg and Wt mice, whereas the ATP contents in Tg mice are lower than the age-matched Wt mice, suggesting that abnormal tissue ATP status may be caused by mitochondrial dysfunction associated with the increased production of ROS [16, 17]. Furthermore, a decrease in energy metabolism in mitochondria may be involved in AD pathogenesis, thereafter leading to a decline in ATP generation [18].…”

Section: Resultsmentioning

confidence: 99%

Characterization of ATP Alternations in an Alzheimer's Disease Transgenic Mouse Model

Zhang

Rissman

Feng

2015

JAD

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Mitochondrial impairment as evidenced by decline in adenosine 5′-triphosphate (ATP) is associated with oxidative stress in Alzheimer’s neuropathology and suggests that mitochondria may fail to maintain cellular energy, through reduced ATP production in neurons. To gain insights into the ATP characteristics of Alzheimer’s disease transgenic (Tg) mice, we investigated ATP contents in the brain and whole blood of Tg mice at three ages (1-, 5- and 24-month-old). Overall, our results demonstrate that tissue ATP contents in Tg mice are significantly reduced, suggesting a decrease of tissue ATP production and mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

“…Among the 15 mammalian StARD-containing proteins, MLN64 was shown to be expressed in all tissues (56,63) and involved in transferring cholesterol from the endolysosomal membrane to the mitochondrial membrane (14,47,65). The N-terminal transmembrane domain called MENTAL (MLN64 N-terminal) targets MLN64 mainly to late endosomes (4,47), and the C-terminal StARD is involved in translocation of MLN64 to mitochondria. Since the MENTAL domain also binds cholesterol, it was suggested that MLN64 captures cholesterol in the endolysosomal compartment and the cytoplasmic StARD then transfers the cholesterol to the mitochondria through interacting with the translocator protein (36,48).…”

Section: Discussionmentioning

confidence: 99%

Cellular Adaptation to Anthrax Lethal Toxin-Induced Mitochondrial Cholesterol Enrichment, Hyperpolarization, and Reactive Oxygen Species Generation through Downregulating MLN64 in Macrophages

Park

Han

et al. 2012

Molecular and Cellular Biology

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To date, the cellular mechanisms of pyroptosis and TIR are largely unknown. We found that LeTx caused NLRP1b/caspase-1-dependent mitochondrial dysfunction, including hyperpolarization and generation of reactive oxygen species, which was distinct from that induced by stimuli such as NLRP3-activating ATP. In TIR cells, these mitochondrial events were not detected, although caspase-1 was activated, in response to LeTx. We identified that downregulation of the late endosomal cholesterol-transferring protein MLN64 in TIR cells was involved in TIR. The downregulation of MLN64 in TIR cells was at least in part due to DNA methyltransferase 1-mediated DNA methylation. In wild-type RAW264.7 cells and primary bone marrow-derived macrophages, LeTx caused NLRP1b/caspase-1-dependent mitochondrial translocation of MLN64, resulting in cholesterol enrichment, membrane hyperpolarization, reactive oxygen species (ROS) generation, and depletion of free glutathione (GSH). This study demonstrates for the first time that MLN64 plays a key role in LeTx/ caspase-1-induced mitochondrial dysfunction.

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STARTing to understand MLN64 function in cholesterol transport

Cited by 17 publications

References 25 publications

An Interactome-Centered Protein Discovery Approach Reveals Novel Components Involved in Mitosome Function and Homeostasis in Giardia lamblia

An Interactome-Centered Protein Discovery Approach Reveals Novel Components Involved in Mitosome Function and Homeostasis in Giardia lamblia

Characterization of ATP Alternations in an Alzheimer's Disease Transgenic Mouse Model

Cellular Adaptation to Anthrax Lethal Toxin-Induced Mitochondrial Cholesterol Enrichment, Hyperpolarization, and Reactive Oxygen Species Generation through Downregulating MLN64 in Macrophages

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