The autophagy–NAD axis in longevity and disease

Wilson, N. J. E.; Kataura, Tetsushi; Korsgen, Miriam E.; Sun, Congxin; Sarkar, Sovan; Korolchuk, Viktor I.

doi:10.1016/j.tcb.2023.02.004

Cited by 25 publications

(18 citation statements)

References 111 publications

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“…It is suggested that SSNX may protect mitochondrial function and morphology, which in turn interferes with MI/RI. Based on these results, we further veri ed whether SSNX could affect mitophagy Autophagy is a metabolic process that degrades macromolecules and can degrade damaged organelles within cells, speci c macromolecules, as well as invading viruses and bacteria [14]. Mitophagy is a type of autophagy that occurs in the mitochondria and is a key process for detecting mitochondrial function and removing damaged or unwanted mitochondria [15].…”

Section: Discussionmentioning

confidence: 99%

Shuangshen Ningxin Capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy:network pharmacology and experiments in vivo

Jia

Chen

Xin

et al. 2023

Preprint

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Background:Myocardial ischemia/reperfusion injury (MI/RI) is a common pathological basis for several cardiovascular diseases, for which no effective treatment exists. Shuangshen Ningxin (SSNX) capsule which is developed by Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine has been demonstrated to alleviate MI/RI, but its mechanism remains to be further elucidated. Methods: The MI/RI miniature pigs model was constructed to evaluate the pharmacodynamics of SSNX by blocking the proximal blood flow of the left anterior descending branch of the cardiac coronary artery through an interventional balloon. The major chemical compounds and potential targets of SSNX were screened by HPLC-MS and SwissTargetPrediction. The targets of MI/RI were identified based on Online Mendelian Inheritance in Man(OMIM) and GeneCards. Cytoscape 3.9.0 was applied to construct a protein-protein interaction (PPI) network, and Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using metascape. To further validate the mechanism of SSNX, Molecular docking, Transmission electron microscopy, and Western blot analysis were used to test the effectiveness of targets in related pathways. Results:The result of experiment in vivo confirmed that SSNX significantly improved cardiac function, attenuated myocardial I/R injury. Through network analysis, a total of 15 active components and 201 targets were obtained from SSNX, 75 of which are potential targets for the treatment of MI/RI. KEGG and MCODE analysis showed that SSNX is involved in the mitophagy signaling pathway, and ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb2 are key components associated with the mitophagy. Further experimental results proved that SSNX protected mitochondrial structure and function, and significantly reduced the expression of mitophagy-related proteins PINK1, Parkin, FUNDC1 and BNIP3 in MI/RI miniature pigs. Conclusion:In this study, the integration of network pharmacology and experiments in vivo demonstrated that SSNX interfered with MI/RI by inhibiting mitophagy.

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Section: Discussionmentioning

confidence: 99%

Shuangshen Ningxin Capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy:network pharmacology and experiments in vivo

Jia

Chen

Xin

et al. 2023

Preprint

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“…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%

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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“…In macroautophagy (which we will refer to as autophagy from now on), these components are sequestered by autophagosomes, which in turn fuse with lysosomes to promote the digestion of cargo such as organelles or proteins 16 . Due to its ability to remove unwanted elements and promote specific or general nutrient availability as an output, autophagy is necessary for quality control, tissue renovation, and metabolic regulation 16–18 …”

Section: Introductionmentioning

confidence: 99%

“…16 Due to its ability to remove unwanted elements and promote specific or general nutrient availability as an output, autophagy is necessary for quality control, tissue renovation, and metabolic regulation. [16][17][18] Ca 2+ ions are known second messengers in metabolic signaling and display an important role in autophagy regulation. [19][20][21] However, the genesis and consequences of Ca 2+ signaling within this regulatory mechanism are very context− dependent and not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation‐induced autophagy through calcium signaling

Ramos,

Serna,

Vilas‐Boas

et al. 2024

The FASEB Journal

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Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+/Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+, and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation‐induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER‐phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.

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The autophagy–NAD axis in longevity and disease

Cited by 25 publications

References 111 publications

Shuangshen Ningxin Capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy:network pharmacology and experiments in vivo

Shuangshen Ningxin Capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy:network pharmacology and experiments in vivo

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

Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation‐induced autophagy through calcium signaling

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