ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

Slavin, Mikhaela; Kumari, Rita; Hood, David A.

doi:10.1016/j.molmet.2022.101623

Cited by 10 publications

(4 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, the Hood research group utilized chronic contractile activity to simulate exercise and observed increased levels of UPRmt-related mRNA and proteins in rat skeletal muscle, and similar results have been observed in murine myocytes [110,111]. Additionally, studies have found that ATF5 plays a critical role in exercise-induced UPRmt and mitochondrial homeostasis because ATF5-knockout muscle displays an enhanced exercise-induced stress kinase signaling response but a blunted UPRmt and mitophagic gene expression response [112]. More recently, our group found that just 12 days of exercise is sufficient for increasing the expression of c-Jun, HSP60, and CLpP in mouse skeletal muscle, which strongly suggests the activation of the classical UPRmt pathway [113].…”

Section: Exercise and The Uprmtmentioning

confidence: 72%

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Wang

Zhang

et al. 2023

Life

View full text Add to dashboard Cite

The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.

show abstract

Section: Exercise and The Uprmtmentioning

confidence: 72%

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Wang

Zhang

et al. 2023

Life

View full text Add to dashboard Cite

show abstract

“…Brains from TMG-treated mice showed high levels of ATF4, with higher ATF4 binding at the ATF5 promoter site initiating the adaptive stress response. ATF4 and ATF5 are required to maintain mitochondrial homeostasis by increasing the transcription of chaperones, proteases, and mitophagy genes ( B’chir et al, 2013 ; Fiorese et al, 2016 ; Slavin et al, 2022 ; Figure 10 ). Thus, OGA inhibition could aid the brain in combatting the accumulation of dysfunctional mitochondria via stimulating ISR mt in mitochondrial diseases.…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4

Alghusen,

Carman,

Wilkins

et al. 2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

BackgroundAccumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer’s disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.MethodsWe used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.ResultsWe show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer’s Disease mice model. The same results are seen in a human in vitro model of AD.ConclusionTogether, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.

show abstract

“…In addition, Slavin and colleagues demonstrated that the Activating Transcription Factor 5 (ATF5) plays a critical role in controlling UPR mt markers in the skeletal muscle of exercised mice. Interestingly, acute exercise triggered the accumulation of ATF5 in the mitochondrial fraction [ 44 ]. In our findings we observed that acutely, exercise increased JNK phosphorylation and ATF5 protein content in the skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase

Gaspar,

Katashima,

Crisol

et al. 2023

Molecular Metabolism

View full text Add to dashboard Cite

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

Cited by 10 publications

References 78 publications

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4

Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase

Contact Info

Product

Resources

About