The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Zaman, Mashiat; Shutt, Timothy E.

doi:10.3389/fcell.2022.858286

Cited by 34 publications

(28 citation statements)

References 177 publications

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“…A dynamic balance between fusion and fission exists in the mitochondrion. Mfn2-mediated fusion forms mitochondrial, whereas Drp1-mediated fission causes mitochondrial fragments to be degraded by mitophagy [34]. A recent study found that the disruption of mitochondrial maintenance was characterized by differently expressed mitochondrial dynein [35].…”

Section: Discussionmentioning

confidence: 99%

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Yang

et al. 2023

J Neuroinflammation

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Objective Patients with hypertension have a risk of depression. Morinda officinalis oligosaccharides (MOOs) have anti-depressant properties. In this study, we aimed to determine whether MOOs can improve the symptoms of depression in individuals with hypertension. Methods Dahl salt-sensitive rats fed with a high-salt diet were stimulated by chronic unpredictable mild stress to mimic hypertension with depression. Primary astrocytes and neurons were isolated from these rats. Astrocytes underwent LPS stimulation to simulate the inflammatory astrocytes during depression. MOOs were administrated at 0.1 mg/g/day in vivo and 1.25, 2.5, and 5 mg/mL in vitro. Mitophagy was inhibited using 5 mM 3-methyladenine (3-MA). Astrocyte-mediated neurotoxicity was detected by co-culturing astrocytes and neurons. Results MOOs decreased systolic pressure, diastolic pressure, and mean arterial pressure, thereby improving depression-like behavior, including behavioral despair, lack of enthusiasm, and loss of pleasure during hypertension with depression. Furthermore, MOOs inhibited inflammation, astrocytic dysfunction, and mitochondrial damage in the brain. Then, MOOs promoted autophagosome and lysosome enriched in mitochondria in LPS-stimulated astrocytes. MOOs suppressed mitochondrial damage and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in astrocytes undergoing LPS stimulation. Importantly, MOOs rescued the impaired neurons co-cultured with astrocytes. The effects of MOOs on LPS-stimulated astrocytes were reversed by 3-MA. Finally, MOOs upregulated LPS-downregulated Mfn2 expression in astrocytes. Mfn2 inhibition partly reversed the effects of MOOs on hypertension with depression. Intriguingly, Mfn2 suppression activated PI3K/Akt/mTOR pathway during MOOs treatment. Conclusions Astrocytes develop neuroinflammation in response to mitochondrial damage during hypertension with depression. MOOs upregulated Mfn2 expression to activate the PI3K/Akt/mTOR pathway-mediated mitophagy, thereby removing impaired mitochondria in astrocytes. Highlights MOOs have anti-hypertensive and anti-depressive properties. MOOs inhibit inflammation and injury in astrocytes during hypertension with depression. MOOs induce mitophagy activation in inflammatory astrocytes with mitochondrial damage. MOOs upregulate Mfn2 expression in astrocytes. Mfn2 activates mitophagy to resist mitochondrial damage in astrocytes.

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Section: Discussionmentioning

confidence: 99%

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Yang

et al. 2023

J Neuroinflammation

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“…To determine whether this branch point variant results in insufficient MFN2 protein levels, we analyzed patient-derived fibroblast cells for hallmarks of MFN2 dysfunction. MFN2 is essential for mitochondrial dynamics, and pathogenic MFN2 variants are associated with diverse mitochondrial phenotypes, including impaired mitochondrial respiration and movement, as well as increased lipid droplet formation 15 . We found that patient-derived fibroblast cells had both increased number and intensity of lipid droplets compared to control cells ( Figure 2 ), which is consistent with the idea that this branch point variant results in insufficient functional MFN2 protein.…”

Section: Resultsmentioning

confidence: 99%

Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A

Stergachis

Blue

Gillentine

et al. 2023

Preprint

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Objectives: Transcript sequencing of patient derived samples has been shown to improve the diagnostic yield for solving cases of likely Mendelian disorders, yet the added benefit of full-length long-read transcript sequencing is largely unexplored. Methods: We applied short-read and full-length isoform cDNA sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis. Results: We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts a branch point critical for intron 6 spicing. Full-length long-read isoform cDNA sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates five distinct altered splicing transcripts. All five altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 protein levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A). Discussion: This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.

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“…Therefore, MFN1 is the main tethering isoform for the fusion of OMMs [ 70 , 71 ]. MFN2 is located on the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and it connects mitochondria to the ER, bringing Ca 2+ influx from the ER to the mitochondria [ 72 , 73 ]. Mitochondrial fission tends to isolate damaged DNA and metabolites in mitochondria.…”

Section: Bas As Regulatory Modulatorsmentioning

confidence: 99%

Role of Microbiota-Modified Bile Acids in the Regulation of Intracellular Organelles and Neurodegenerative Diseases

Kiriyama

Nochi

2023

Genes

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Bile acids (BAs) are amphiphilic steroidal molecules generated from cholesterol in the liver and facilitate the digestion and absorption of fat-soluble substances in the gut. Some BAs in the intestine are modified by the gut microbiota. Because BAs are modified in a variety of ways by different types of bacteria present in the gut microbiota, changes in the gut microbiota can affect the metabolism of BAs in the host. Although most BAs absorbed from the gut are transferred to the liver, some are transferred to the systemic circulation. Furthermore, BAs have also been detected in the brain and are thought to migrate into the brain through the systemic circulation. Although BAs are known to affect a variety of physiological functions by acting as ligands for various nuclear and cell-surface receptors, BAs have also been found to act on mitochondria and autophagy in the cell. This review focuses on the BAs modified by the gut microbiota and their roles in intracellular organelles and neurodegenerative diseases.

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The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Cited by 34 publications

References 177 publications

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A

Role of Microbiota-Modified Bile Acids in the Regulation of Intracellular Organelles and Neurodegenerative Diseases

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