Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids

Chen, Qun; Kovilakath, Anna; Allegood, Jeremy C.; Thompson, Jeremy; Hu, Ying; Cowart, L. Ashley; Lesnefsky, Edward J.

doi:10.1016/j.bbalip.2023.159366

Cited by 4 publications

(2 citation statements)

References 59 publications

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“…The de novo ceramide synthesis initiates in the cytoplasmic leaflet of the ER membrane, and ceramide plays a key role in regulating membrane thickness and stability ( Venkatesan et al, 2023 ). Ceramide accumulation induces ER stress by increasing protein misfolding and aggregation, and perturbs calcium signaling in the ER ( Boslem et al, 2013 ; Chen et al, 2023 ). In INS-1 cells, Ceramide promotes ER stress and affects the synthesis and release of insulin ( Lei et al, 2008 ).…”

Section: Abnormal Ceramide Metabolism Leads To the Pathogenesis Of T2dmmentioning

confidence: 99%

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Pan,

Li,

Lin

et al. 2024

Front. Pharmacol.

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The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

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Section: Abnormal Ceramide Metabolism Leads To the Pathogenesis Of T2dmmentioning

confidence: 99%

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Pan,

Li,

Lin

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…ER stress is implicated in a wide range of human diseases [21,22], such as diabetes [23], non-alcoholic fatty acid disease [24], inflammations (including heart diseases [25] and inflammatory bowel disease [26,27]), neurodegeneration (Parkinson's disease [28], Alzheimer's disease [29] and Huntington's disease [30,31]) and also psychiatric diseases [32,33]. Since defects in the proper functioning of the ER are observed in most human diseases and the frequency of ER stress is also increased during aging [34][35][36], it is crucial to study and understand the dynamic behaviour of the regulatory system as comprehensively as possible.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Kapuy

2024

IJMS

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Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.

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Aging-induced mitochondrial dysfunction: two distinct populations of mitochondria versus a combined population

Chen,

Thompson,

et al. 2024

American Journal of Physiology-Heart and Circulatory Physiology

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Mitochondrial function in aged hearts is impaired, and studies of isolated mitochondria are commonly used to assess their function. The two populations of cardiac mitochondria, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), are affected by aging. However, the yield of these mitochondria, particularly SSM, is limited in the mouse heart due to the smaller heart size. To address this issue, the authors developed a method to isolate a mixed population (MIX) of SSM and IFM mitochondria from a single mouse heart. The aim of the study was to compare the mitochondrial function between SSM, IFM, and the MIX population from young and aged mouse hearts. The MIX population had a higher yield of total protein and citrate synthase activity from both young and aged hearts compared to the individual yields of SSM or IFM. OXPHOS was decreased in aged SSM and IFM compared to young SSM and IFM, as well as in the MIX population isolated from aged hearts compared to young hearts, when using complex I or complex IV substrates. Furthermore, aging barely affected the sensitivity to MPTP opening in SSM, whereas the sensitivity was increased in IFM isolated from aged hearts and in the MIX population from aged hearts compared to the corresponding populations isolated from young hearts. These results suggest that mitochondrial dysfunction exists in aged hearts, and the isolation of a MIX population of mitochondria from the mouse heart is a potential approach to study mitochondrial function in the mouse heart.

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Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids

Cited by 4 publications

References 59 publications

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Aging-induced mitochondrial dysfunction: two distinct populations of mitochondria versus a combined population

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