Rapamycin Ameliorates Cognitive Impairments and Alzheimer’s Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice

Ding, Yuanting; Liu, Heng; Cen, Mofei; Yu-xiang, Tao; Lai, Chencen; Tang, Zhi

doi:10.1007/s11064-020-03160-6

Cited by 22 publications

(12 citation statements)

References 45 publications

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“…In the hippocampus of type 2 diabetic mice and high glucose cultured human SK cells, GSK3β was activated to promote the significant expression and mitochondrial translocation of Drp1, which exacerbated mitochondrial fission and subsequently damaged the morphology and function of mitochondria [30]. Interestingly, levels of Mfn1, Mfn2, OPA1 were not altered in diabetic hippocampus, which was consistent with some research results [30,69,158]. However, some studies report that Opa1 was reduced in the cortex of GK mice with T2DM [159].…”

Section: Mitochondrial Dynamicssupporting

confidence: 86%

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

et al. 2022

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Type 2 diabetes (T2DM) is a well known risk factor for Alzheimer’s disease. Mitochondria are the center of intracellular energy metabolism and the main source of reactive oxygen species. Mitochondrial dysfunction has been identified as a key factor in diabetes-associated brain alterations contributing to neurodegenerative events. Defective insulin signaling may act in concert with neurodegenerative mechanisms leading to abnormalities in mitochondrial structure and function. Mitochondrial dysfunction triggers neuronal energy exhaustion and oxidative stress, leading to brain neuronal damage and cognitive impairment. The normality of mitochondrial function is basically maintained by mitochondrial quality control mechanisms. In T2DM, defects in the mitochondrial quality control pathway in the brain have been found to lead to mitochondrial dysfunction and cognitive impairment. Here, we discuss the association of mitochondrial dysfunction with T2DM and cognitive impairment. We also review the molecular mechanisms of mitochondrial quality control and impacts of mitochondrial quality control on the progression of cognitive impairment in T2DM.

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Section: Mitochondrial Dynamicssupporting

confidence: 86%

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

et al. 2022

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“…However, rapamycin alleviates AD-related protein aggregation and learning deficits in these rat models through inhibition of AMPK-mTOR signaling (Sun et al 2019 ). An independent study further supported these results in STZ-induced T2DM rats (Ding et al 2021 ). STZ leads to hyperactivation of the mTOR/p70S6k pathway, which can be attenuated by rapamycin treatment.…”

Section: Autophagy In Diseasementioning

confidence: 61%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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“…In order to prove the selectivity of this process in vivo , we used a mouse model where mtDNA alterations rapidly accumulate and indeed, activation of the mTORC1 pathway by rapamycin was able to eliminate abnormal mtDNA molecules and thus reduces the accumulation of cells with mitochondrial dysfunction. Rapamycin has been described as a potential treatment against mitochondrial diseases 18,63 , however, since we observed a fiber-type shift, mTORC1 inhibition might activate other signalling pathways with undesirable effects. Nonetheless, by using Rapamycin we demonstrated that elimination of mutant mtDNA without affecting total mtDNA copy number is possible.…”

Section: Discussionmentioning

confidence: 67%

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Pla‐Martín

Sen

Kallabis

et al. 2021

Preprint

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Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria together with mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here we show that mtDNA depletion after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, is due to an exacerbated mtDNA turnover. Targeting of nucleoids is controlled by Twinkle which, together with the mitochondrial transmembrane proteins ATAD3 and SAMM50, orchestrate mitochondrial membrane remodeling to form extrusions. mtDNA removal depends on autophagy and requires the vesicular trafficking protein VPS35 which binds to Twinkle-enriched mitochondrial subcompartments upon mtDNA damage. Stimulation of autophagy by rapamycin selectively removes mtDNA deletions which accumulated during muscle regeneration in vivo, but without affecting mtDNA copy number. With these results we unveil a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network. We reveal the molecular targets involved in a process with multiple potential benefits against human mtDNA related diseases, either inherited, acquired or due to normal ageing.

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Rapamycin Ameliorates Cognitive Impairments and Alzheimer’s Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice

Cited by 22 publications

References 45 publications

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

Protein clearance strategies for disease intervention

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

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