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Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.

ABSTRACT: Calcium (Ca2+) homeostasis is essential for neuronal function and survival. Altered Ca2+ homeostasis has been consistently observed in neurological diseases. How Ca2+ homeostasis is achieved in various cellular compartments of disease-relevant cell types is not well understood. Here we show in Drosophila Parkinson's disease (PD) models that Ca2+ transport from the endoplasmic reticulum (ER) to mitochondria through the ER-mitochondria contact site (ERMCS) critically regulates mitochondrial Ca2+ (mito-Ca2+) homeostasis in dopaminergic (DA) neurons, and that the PD-associated PINK1 protein modulates this process. In PINK1 mutant DA neurons, the ERMCS is strengthened and mito-Ca2+ level is elevated, resulting in mitochondrial enlargement and neuronal death. Miro, a well-characterized component of the mitochondrial trafficking machinery, mediates the effects of PINK1 on mito-Ca2+ and mitochondrial morphology, apparently in a transport-independent manner. Miro overexpression mimics PINK1 loss-of-function effect, whereas inhibition of Miro or components of the ERMCS, or pharmacological modulation of ERMCS function, rescued PINK1 mutant phenotypes. Mito-Ca2+ homeostasis is also altered in the LRRK2-G2019S model of PD and the PAR-1/MARK model of neurodegeneration, and genetic or pharmacological restoration of mito-Ca2+ level is beneficial in these models. Our results highlight the importance of mito-Ca2+ homeostasis maintained by Miro and the ERMCS to mitochondrial physiology and neuronal integrity. Targeting this mito-Ca2+ homeostasis pathway holds promise for a therapeutic strategy for neurodegenerative diseases.

SUBMITTER: Lee KS

PROVIDER: S-EPMC6156612 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.

Lee Kyu-Sun KS Huh Sungun S Lee Seongsoo S Wu Zhihao Z Kim Ae-Kyeong AK Kang Ha-Young HY Lu Bingwei B

Proceedings of the National Academy of Sciences of the United States of America 20180905 38

Calcium (Ca2+) homeostasis is essential for neuronal function and survival. Altered Ca2+ homeostasis has been consistently observed in neurological diseases. How Ca2+ homeostasis is achieved in various cellular compartments of disease-relevant cell types is not well understood. Here we show in Drosophila Parkinson's disease (PD) models that Ca2+ transport from the endoplasmic reticulum (ER) to mitochondria through the ER-mitochondria contact sit ...[more]

PMID: 30185553

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Project description:Mutations in the macroautophagy/autophagy gene WDR45 cause β-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.Abbreviations: 7-ADD: 7-aminoactinomycin D; ASD: autistic spectrum disorder; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; BCAP31: B cell receptor associated protein 31; BPAN: β-propeller protein-associated neurodegeneration; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CDIPT: CDP-diacylglycerol-inositol 3-phosphatidyltransferase (phosphatidylinositol synthase); DDIT3/CHOP: DNA-damage inducible transcript 3; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HIP: hippocampus; HSPA5/GRP78: heat shock protein family A (HSP70) member 5; KO: knockout; LAMP1: lysosomal-associated membrane 1; mEPSCs: miniature excitatory postsynaptic currents; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MIB: mid-brain; MTOR: mechanistic target of rapamycin kinase; PCR: polymerase chain reaction; PFA: paraformaldehyde; PFC: prefrontal cortex; PRM: parallel reaction monitoring; RBFOX3/NEUN: RNA binding protein, fox-1 homolog [C. elegans] 3; RTN3: reticulon 3; SEC22B: SEC22 homolog B, vesicle trafficking protein; SEC61B: SEC61 translocon beta subunit; SEM: standard error of the mean; SNR: substantia nigra; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; Tm: tunicamycin; TMT: tandem mass tag; TUDCA: tauroursodeoxycholic acid; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UPR: unfolded protein response; WDR45: WD repeat domain 45; WT: wild type; XBP1: X-box binding protein 1.

Project description:Hyperglycemia in diabetes mellitus (DM) patients is a causative factor for amyloidogenesis and induces neuropathological changes, such as impaired neuronal integrity, neurodegeneration, and cognitive impairment. Regulation of mitochondrial calcium influx from the endoplasmic reticulum (ER) is considered a promising strategy for the prevention of mitochondrial ROS (mtROS) accumulation that occurs in the Alzheimer's disease (AD)-associated pathogenesis in DM patients. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A has received an increasing amount of attention as a novel candidate with anti-oxidative and neuroprotective effects in AD. Here, we investigated the effect of urolithin A on high glucose-induced amyloidogenesis caused by mitochondrial calcium dysregulation and mtROS accumulation resulting in neuronal degeneration. We also identified the mechanism related to mitochondria-associated ER membrane (MAM) formation. We found that urolithin A-lowered mitochondrial calcium influx significantly alleviated high glucose-induced mtROS accumulation and expression of amyloid beta (Aβ)-producing enzymes, such as amyloid precursor protein (APP) and β-secretase-1 (BACE1), as well as Aβ production. Urolithin A injections in a streptozotocin (STZ)-induced diabetic mouse model alleviated APP and BACE1 expressions, Tau phosphorylation, Aβ deposition, and cognitive impairment. In addition, high glucose stimulated MAM formation and transglutaminase type 2 (TGM2) expression. We first discovered that urolithin A significantly reduced high glucose-induced TGM2 expression. In addition, disruption of the AIP-AhR complex was involved in urolithin A-mediated suppression of high glucose-induced TGM2 expression. Markedly, TGM2 silencing inhibited inositol 1, 4, 5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion-selective channel protein 1 (VDAC1) interactions and prevented high glucose-induced mitochondrial calcium influx and mtROS accumulation. We also found that urolithin A or TGM2 silencing prevented Aβ-induced mitochondrial calcium influx, mtROS accumulation, Tau phosphorylation, and cell death in neuronal cells. In conclusion, we suggest that urolithin A is a promising candidate for the development of therapies to prevent DM-associated AD pathogenesis by reducing TGM2-dependent MAM formation and maintaining mitochondrial calcium and ROS homeostasis.

Dataset Information

Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.

Publications

Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.

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