O-GlcNAcylation of SIRT1 Protects against Cold Stress-Induced Skeletal Muscle Damage via Amelioration of Mitochondrial Homeostasis

Cao, Yu; Zhang, Meng; Li, Ye; Lu, Jingjing; Zhou, Wanhui; Li, Xiaoshuang; Shi, Hao; Xu, Bin; Li, Shize

doi:10.3390/ijms232314520

Cited by 7 publications

(5 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OSMI-1 significantly increased ROS-induced endoplasmic reticulum (ER) stress, resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria [92]. Deletion of the OGT gene aggravated the homeostatic imbalance and oxidative stress in mitochondria induced by cold stress in skeletal muscle [93]. Jóźwiak et al reported that the increased expression of mOGT affects the mitochondrial transmembrane potential and increases the production of mROS.…”

Section: Mitochondrial Oxidative Stressmentioning

confidence: 99%

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Qiu,

Cui,

Huang

et al. 2024

Antioxidants

View full text Add to dashboard Cite

Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

show abstract

Section: Mitochondrial Oxidative Stressmentioning

confidence: 99%

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Qiu,

Cui,

Huang

et al. 2024

Antioxidants

View full text Add to dashboard Cite

show abstract

“…O‐GlcNAcylation of SIRT1 ( Figure ) acts to define its spatiotemporal distribution between the nucleus and cytoplasm, and thus, its functionality, 65 and conversely, SIRT1 and NAD+ (the primary driver of SIRT1 activity) act to diminish O‐GlcNAcylation through inhibition of OGT 66,67 . During states of acute stress, O‐GlcNAcylation of SIRT1 enhances its ability to reduce cellular apoptosis 68,69 . In contrast, during nutrient surplus, O‐GlcNAcylation of SIRT1 reduces its interactions with PGC‐1α and promotes its nuclear exclusion and proteosomal degradation 65 .…”

Section: Interaction Of Udp‐glcnac With Other Nutrient‐sensitive Sign...mentioning

confidence: 99%

“…64 O-GlcNAcylation of SIRT1 (Figure 3) acts to define its spatiotemporal distribution between the nucleus and cytoplasm, and thus, its functionality, 65 and conversely, SIRT1 and NAD+ (the primary driver of SIRT1 activity) act to diminish O-GlcNAcylation through inhibition of OGT. 66,67 68,69 In contrast, during nutrient surplus, O-GlcNAcylation of SIRT1 reduces its interactions with PGC-1α and promotes its nuclear exclusion and proteosomal degradation. 65 Enhanced glucose entry and O-GlcNAcylation suppresses the expression of PGC-1α 70 and negates the actions of PGC-1α to promote the use of ketone bodies as a myocardial fuel.…”

Section: Interplay Of O-glcnacylation and Nutrient Deprivation Sensor...mentioning

confidence: 99%

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

Packer

2023

European J of Heart Fail

View full text Add to dashboard Cite

The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia‐inducible factor‐1α (HIF‐1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin‐1 (SIRT1) and adenosine monophosphate‐activated protein kinase (AMPK), which promote fatty‐acid oxidation and the substantial mitochondrial ATP production required for survival in a high‐workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct – uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) – functions as a critical nutrient surplus sensor. UDP‐GlcNAc drives the post‐translational protein modification known as O‐GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O‐GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O‐GlcNAcylation is regulated by only two enzymes, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), which adds or removes GlcNAc (N‐acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O‐GlcNAcylation, both experimentally and clinically. Heightened O‐GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage‐gated sodium channels and Ca2+/calmodulin‐dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O‐GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O‐GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O‐GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP‐GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF‐1α) can promote the development of cardiomyopathy.

show abstract

“…105 During states of acute stress, O-GlcNAcylation of SIRT1 enhances its effects on organellar and cellular health. 106,107 By contrast, during nutrient surplus states seen in chronic stress, O-GlcNAcylation of SIRT1 promotes its nuclear exclusion and proteosomal degradation. 104 At the same time, there is an intimate interplay between UDP-GlcNAc and PI3K/AKT/mTOR because both are upregulated by nutrient surplus (Figure 2).…”

Section: Protein Modification By O-glcnacylationmentioning

confidence: 99%

Section: O-glcnacylation By Uridine Diphosphate N-acetylglucosaminementioning

confidence: 99%

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Packer

2023

JASN

View full text Add to dashboard Cite

Fetal kidneys have increased uptake of glucose, ATP production by glycolysis, and upregulation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α). These interacting processes promote nephrogenesis in a hypoxic low-tubular-workload environment. In contrast, the healthy adult kidney upregulates sirtuin-1 and adenosine monophosphate-activated protein kinase, which enhances ATP production through fatty-acid oxidation, in a normoxic high-tubular-workload environment. During stress or injury, the kidney reverts to a fetal signaling program that is adaptive in the short-term, but deleterious if sustained with heightened oxygen tension and tubular workloads. Prolonged increase in glucose uptake in glomerular and proximal tubular cells leads to enhanced flux through the hexosamine biosynthesis pathway. The endproduct — uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) — drives the rapid and reversible O-GlcNAcylation of thousands of intracellular proteins, most not membrane-bound or secreted. O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas hundreds of kinases and phosphatases regulate phosphorylation, only O-GlcNAc transferase and O-GlcNAcase, which add or remove O-GlcNAc from target proteins, regulate O-GlcNAcylation. Fetal reprogramming (upregulating mTOR and HIF-1α) and increased O-GlcNAcylation occur in diabetic and nondiabetic CKD, experimentally and clinically. Augmentation of O-GlcNAcylation in the adult kidney enhances oxidative stress, cell cycle entry, and apoptosis, activates proinflammatory and profibrotic pathways, and inhibits megalin-mediated albumin endocytosis in glomerular mesangial and proximal tubular cells, which muting of O-GlcNAcylation can aggravate and attenuate, respectively. Additionally, some nephroprotective drugs are associated with diminished O-GlcNAcylation in the kidney. Evidence supports further investigation of UDP-GlcNAc as a critical nutrient surplus sensor in the development of diabetic and nondiabetic CKD.

show abstract

O-GlcNAcylation of SIRT1 Protects against Cold Stress-Induced Skeletal Muscle Damage via Amelioration of Mitochondrial Homeostasis

Cited by 7 publications

References 90 publications

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Contact Info

Product

Resources

About