Autophagy promotes cell survival by maintaining NAD levels

Kataura, Tetsushi; Sedlackova, Lucia; Otten, Elsje G.; Kumari, Ruchika; Shapira, David; Scialò, Filippo; Stefanatos, Rhoda; Ishikawa, Keiichi; Kelly, George; Sun, Congxin; Maetzel, Dorothea; Kenneth, Niall S.; Trushin, Sergey; Zhang, Tong; Trushina, Eugenia; Bascom, Charles C.; Tasseff, Ryan; Isfort, Robert J.; Oblong, John E.; Miwa, Soichi; Lazarou, Michael; Jaenisch, Rudolf; Imoto, Masaya; Saiki, Sachio; Papamichos‐Chronakis, Manolis; Manjithaya, Ravi; Maddocks, Oliver D.K.; Sanz, Alberto; Sarkar, Sovan; Korolchuk, Viktor I.

doi:10.1016/j.devcel.2022.10.008

Cited by 47 publications

(29 citation statements)

References 58 publications

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“…A recent study in a mouse model of the related condition Krabbe disease demonstrated that inhibition of the mTOR pathway with rapamycin enhanced autophagy, reduced inflammation and attenuated leukodystrophy [35]. These findings are consistent with our observations in Niemann-Pick Type C1, where neurodegeneration was reduced by enhancing autophagy through an effect on NAD levels [17]. The association between neuroinflammation, autophagy dysfunction and mTOR activation in MLD, combined with previous findings demonstrating a beneficial effect on these parameters by activating autophagy, could lead one to speculate that enhancing autophagy and/or inhibiting mTOR activation could be an effective strategy in MLD.…”

Section: Discussionsupporting

confidence: 92%

“…The mTOR pathway plays a critical role in negatively regulating the cellular catabolic process of autophagy, a process which maintains metabolic homeostasis by recycling sub-cellular components [15]. Dysfunction of autophagy has been previously demonstrated to induce metabolic deficits leading to cellular death, and thus the dysfunction of this process has critical and detrimental effects on cellular health [16][17][18].…”

Section: Deficient Autophagy In Mldmentioning

confidence: 99%

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Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

Catchpole,

Hartanto,

Kataura

et al. 2023

Preprint

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Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder typically resulting from bi-allelic loss-of-function variants in the ARSA gene which encodes the lysosomal enzyme, arylsulphatase A, leading to the accumulation of its substrate, sulphatide, and widespread demyelination. Although gene therapy is available for MLD, it is limited by high cost and a narrow window for intervention, which means the development of therapies for MLD remains a key goal. The aim of the present study was to explore disease mechanisms in MLD with a view to identifying novel targets for therapeutic intervention for patients who cannot avail of gene therapy. Post-mortem globus pallidus and dentate nucleus tissue was obtained from MLD cases (N=5; age 2-33 years old) and compared to age-, sex- and ethnicity- matched controls (N=5) and studied using discovery proteomics which demonstrated a marked inflammatory response, activation of the mTOR pathway, oxidative stress and metabolic remodelling in MLD cases. Histological analysis of inflammatory markers, including the terminal fragment of complement pathway activation, C3d, and the secreted glycoprotein YKL-40, a commonly used biomarker for inflammation, demonstrated their enrichment in MLD cases. Given that the mTOR pathway plays a key role in supressing autophagy, we next investigated autophagy and identified the accumulation of autophagosomes in MLD cases, consistent with deficient autophagy. Taken together, these findings suggest inflammation and autophagy dysfunction are key processes involved in MLD and that the mTOR pathway could be a novel therapeutic target for MLD.

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Section: Discussionsupporting

confidence: 92%

Section: Deficient Autophagy In Mldmentioning

confidence: 99%

Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

Catchpole,

Hartanto,

Kataura

et al. 2023

Preprint

Self Cite

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“…Therefore, they can strongly contribute to energetics failure in neurons. Moreover, autophagy/mitophagy defects can per se cause neurodegeneration by depleting NAD pools [ 118 ].…”

Section: Rab Proteins At the Crossroads Of Mitochondrial Dysfunction ...mentioning

confidence: 99%

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases

Shafique

Brughera

Lualdi

et al. 2023

IJMS

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Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause–effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.

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“…These pathways are initiated and characterized by multiple stimuli and signaling mediators [14,15]. The main function of autophagy relates to the cell's protection and survival, while under some situations it leads to cell death [16,17]. There are different molecular pathways for crosstalk between the apoptosis and autophagy pathways [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Temozolomide, Simvastatin and Acetylshikonin Combination Induces Mitochondrial Dependent Apoptosis in GBM Cells which is Regulated by Autophagy

Hajiahmadi¹,

Lorzadeh²,

Iranpour³

et al. 2023

Preprint

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Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of TMZ and cholesterol lowering medications (statins) is currently under investigation in in vivo and clinical trials. In our current investigation, we have used a triple combination therapy of TMZ, Simvastatin (Simva), and Acetylshikonin (ASH) and investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used viability, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. Our results showed that TMZ/Simva/ASH combination therapy significantly induced more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage (increase of ROS, decrease of MMP) and induced caspase-3/7 activation in both GBM cell lines. Compared to all single treatments and the TMZ/Simva treatment, TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment was due to partial inhibition of autophagy flux (accumulation of LC3β-II and decrease in p62 degradation) in GBM cells. Our investigation also showed that TMZ/Simva/ASH-induced cell death was depended on autophagy flux as further inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially depends on an increase of Bax expression in GBM cells. Our current investigation might open new avenues for more effective treatment of GBM but further investigations are required for better identification of the mechanisms.

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Autophagy promotes cell survival by maintaining NAD levels

Cited by 47 publications

References 58 publications

Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases

Temozolomide, Simvastatin and Acetylshikonin Combination Induces Mitochondrial Dependent Apoptosis in GBM Cells which is Regulated by Autophagy

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