Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations

Chen, Anbin; Kristiansen, Cecilie Katrin; Hong, Yu; Kianian, Atefeh; Fang, Evandro Fei; Sullivan, Gareth J.; Wang, Jian; Li, Xingang; Bindoff, Laurence A.; Liang, Kristina Xiao

doi:10.3389/fcell.2021.737304

Cited by 18 publications

(22 citation statements)

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“…Our study not only revealed the loss of neurons but also highlighted the presence of astrocyte activation and reactive gliosis in patient-derived organoids. The observed astrocyte activation is particularly significant as it has been shown in our study [43] and previous research [44] to be associated with neuronal toxicity and may contribute to the neural loss observed in POLG-related disorders. Astrocytes play crucial roles in supporting neuronal function and maintaining brain homeostasis.…”

Section: Discussionsupporting

confidence: 69%

“…In the realm of therapeutic interventions for POLG-associated disorders, the role of metformin as a treatment option has garnered considerable attention. Building on our previous work, we’ve substantiated its effectiveness through an array of tests [28]. A closer examination of metformin’s potential therapeutic pathways reveals its intimate association with mitochondrial operations and cellular metabolic processes.…”

Section: Resultsmentioning

confidence: 88%

“…According to prior studies, metformin could alleviate neuronal damage/loss, encourage neuronal differentiation, and suppress astrocyte formation in a cerebral ischemia/reperfusion rat model [35]. We, along with others, have found that metformin fosters mitochondrial biogenesis and bolsters mitochondrial activity and function [28, 36]. Thus, we asked if metformin could mitigate the phenotype and molecular profile of the POLG-organoid.…”

Section: Resultsmentioning

confidence: 99%

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Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids

Chen,

Yangzom,

Hong

et al. 2023

Preprint

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In our research, we developed a 3D brain organoid model to study POLG-related encephalopathy, a mitochondrial disease stemming from POLG gene mutations. We utilized induced pluripotent stem cells (iPSCs) derived from patients with these mutations to generate cortical organoids, which exhibited typical POLG disease features, such as altered morphology, neuronal loss, and mtDNA depletion. We also identified significant dysregulation in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK-STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory DA GLU neurons. This novel model effectively mirrors both the molecular and pathological attributes of POLG disease, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG-related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids

Chen,

Yangzom,

Hong

et al. 2023

Preprint

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“…Functional validation studies using appropriate in vitro disease models recapitulating the neuropathological features of mitochondrial epilepsy, including parvalbumin+ interneuron vulnerability, should also be performed to overcome the limitations of using postmortem tissues to determine the cause and effect of parvalbumin+ interneuron dysfunction and degeneration [32]. Suitable models could then be utilised to test novel therapies which improve the functioning of parvalbumin+ interneurons and consider the interactions with nonneuronal cells including astrocytes which potentially have a neuropathological role in POLG-related disease [32,62,63]. It is likely that novel treatments targeting mitochondria to prevent the dysfunction of these highly important organelles and to preserve the functioning of parvalbumin+ interneurons may benefit an array of patients with common epilepsies and neurodevelopmental disorders.…”

Section: Future Perspectivesmentioning

confidence: 99%

Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome

Smith

Erskine

Blain

et al. 2022

Neuropathology Appl Neurobio

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Aims: Alpers' syndrome is a severe neurodegenerative disease typically caused by bi-allelic variants in the mitochondrial DNA (mtDNA) polymerase gene, POLG, leading to mtDNA depletion. Intractable epilepsy, often with an occipital focus, and extensive neurodegeneration are prominent features of Alpers' syndrome. Mitochondrial oxidative phosphorylation (OXPHOS) is severely impaired with mtDNA depletion and is likely to be a major contributor to the epilepsy and neurodegeneration in Alpers' syndrome. We hypothesised that parvalbumin-positive(+) interneurons, a neuronal class critical for inhibitory regulation of physiological cortical rhythms, would be particularly vulnerable in Alpers' syndrome due to the excessive energy demands necessary to sustain their fast-spiking activity.Methods: We performed a quantitative neuropathological investigation of inhibitory interneuron subtypes (parvalbumin+, calretinin+, calbindin+, somatostatin interneurons+) in postmortem neocortex from 14 Alpers' syndrome patients, five sudden unexpected death in epilepsy (SUDEP) patients (to control for effects of epilepsy) and nine controls.Results: We identified a severe loss of parvalbumin+ interneurons and clear evidence of OXPHOS impairment in those that remained. Comparison of regional abundance of interneuron subtypes in control tissues demonstrated enrichment of parvalbumin+ interneurons in the occipital cortex, while other subtypes did not exhibit such topographic specificity.Conclusions: These findings suggest that the vulnerability of parvalbumin+ interneurons to OXPHOS deficits coupled with the high abundance of parvalbumin+ interneurons in the occipital cortex is a key factor in the aetiology of the occipital-predominant epilepsy that characterises Alpers' syndrome. These findings provide novel insights into Alpers' syndrome neuropathology, with important implications for the development of preclinical models and disease-modifying therapeutics.

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“…19 Mitochondria-specific autophagy (mitophagy), a cellular catabolic process targeting damaged mitochondria, holds a prominent role in mitochondrial quality control 20 and is dysregulated in aortic aneurysms. 21,22 Chen et al 23 showed that both treatment with NR or with metformin, an antidiabetic drug that enhances autophagy, rescued mitophagy defects and mitochondrial function in mitochondrial DNA polymerase gamma (POLG)-mutant cells. In fact, there is strong evidence about the protective effect of metformin on abdominal aortic aneurysm growth and rupture in humans and ApoE-mouse models.…”

Section: Resultsmentioning

confidence: 99%

Rewiring Vascular Metabolism Prevents Sudden Death due to Aortic Ruptures—Brief Report

Oller

Gabandé‐Rodríguez

Roldán-Montero

et al. 2022

ATVB

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Background: The goal of this study was to determine whether boosting mitochondrial respiration prevents the development of fatal aortic ruptures triggered by atherosclerosis and hypertension. Methods: Ang-II (angiotensin-II) was infused in ApoE (Apolipoprotein E)-deficient mice fed with a western diet to induce acute aortic aneurysms and lethal ruptures. Results: We found decreased mitochondrial respiration and mitochondrial proteins in vascular smooth muscle cells from murine and human aortic aneurysms. Boosting NAD levels with nicotinamide riboside reduced the development of aortic aneurysms and sudden death by aortic ruptures. Conclusions: Targetable vascular metabolism is a new clinical strategy to prevent fatal aortic ruptures and sudden death in patients with aortic aneurysms.

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Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations

Abstract: Graphical AbstractHypothetical mechanisms of mitophagy dysfunction in POLG-mutant astrocytes.

Cited by 18 publications

References 58 publications

Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids

Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids

Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome

Rewiring Vascular Metabolism Prevents Sudden Death due to Aortic Ruptures—Brief Report

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