Mitochondrial respiration links TOR complex 2 signaling to calcium regulation and autophagy

Vlahakis, Ariadne; Muniozguren, Nerea Lopez; Powers, Ted

doi:10.1080/15548627.2017.1299314

Cited by 13 publications

(6 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mammalian target of rapamycin complex 2 (mTORC2) pathway was shown to participate in protecting the heart from ischaemic injury, cell proliferation and differentiation [2,3]. Furthermore, mTORC2 regulates mitochondrial reactive oxygen species (ROS) and mitochondrial respiration [4]. Rictor is a core component of mTORC2 [5].…”

Section: Introductionmentioning

confidence: 99%

Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43

et al. 2021

View full text Add to dashboard Cite

Rictor is a key component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for Akt phosphorylation (Ser473). Our previous study shows that knockdown of Rictor prevents cardiomyocyte differentiation from mouse embryonic stem (ES) cells and induces abnormal electrophysiology of ES cell-derived cardiomyocytes (ESC-CMs). Besides, knockdown of Rictor causes down-expression of connexin 43 (Cx43), the predominant gap junction protein, that is located in both the sarcolemma and mitochondria in cardiomyocytes. Mitochondrial Cx43 (mtCx43) plays a crucial role in mitochondrial function. In this study, we used the model of cardiomyocyte differentiation from mouse ES cells to elucidate the mechanisms for the mitochondrial damage in ESC-CMs after knockdown of Rictor. We showed swollen and ruptured mitochondria were observed after knockdown of Rictor under transmission electron microscope. ATP production and mitochondrial transmembrane potential were significantly decreased in Rictor-knockdown cells. Furthermore, knockdown of Rictor inhibited the activities of mitochondrial respiratory chain complex. The above-mentioned changes were linked to inhibiting the translocation of Cx43 into mitochondria by knockdown of Rictor. We revealed that knockdown of Rictor inactivated the mTOR/Akt signalling pathway and subsequently decreased HDAC6 expression, resulted in Hsp90 hyper-acetylation caused by HDAC6 inhibition, thus, inhibited the formation of Hsp90-Cx43-TOM20 complex. In conclusion, the mitochondrial Cx43 participates in shRNA-Rictor-induced mitochondrial function damage in the ESC-CMs.

show abstract

Section: Introductionmentioning

confidence: 99%

Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43

et al. 2021

View full text Add to dashboard Cite

show abstract

“…RICTOR is a core component of mTORC2 (Oh & Jacinto, 2011). Furthermore, mTORC2 regulates mitochondrial respiration and reactive oxygen species (Vlahakis et al, 2017). SIRT3, a major mitochondrial nicotinamide adenine dinucleotide (NAD)‐dependent deacetylase, controls the rate of mitochondrial ATP generation by regulating the activity and amount of mitochondrial respiration and oxidative phosphorylation (Giralt & Villarroya, 2012).…”

Section: Discussionmentioning

confidence: 99%

Deterioration of mitochondrial biogenesis and degradation in the endometrium is a cause of subfertility in cows

Matsuyama

Nakamura

Minabe

et al. 2023

Molecular Reproduction Devel

View full text Add to dashboard Cite

To investigate possible causes of reproductive failure, we conducted global endometrial gene expression analyses in fertile and subfertile cows. Ingenuity pathway analysis showed that RICTOR and SIRT3 are significant upstream regulators for highly expressed genes in fertile cows, and are predicted to be activated upstream regulators of normal mitochondrial respiration. Canonical pathway analysis revealed that these highly expressed genes are involved in the activation of mitochondrial oxidative phosphorylation. Therefore, in subfertile cows, the inactivation of RICTOR and SIRT3 may correlate with decreased capacity of mitochondrial respiration. Furthermore, the expression levels of most mitochondrial DNA genes and nuclear genes encoding mitochondrial proteins were higher in subfertile cows. The mitochondrial DNA copy number was significantly higher in the endometrium of subfertile cows, whereas the ATP content did not differ between fertile and subfertile cows. Quantitative reverse transcription‐PCR analysis demonstrated that the expression of PGC1a, TFAM, MFN1, FIS1, and BCL2L13 were significantly lower in subfertile cows. In addition, transmission electron microscopy images showed mitochondrial swelling in the endometrial cells of the subfertile cow. These results suggest that poor‐quality mitochondria accumulate in the endometrium owing to a reduced capacity for mitochondrial biogenesis, fusion, fission, and degradation in subfertile cows, and may contribute to infertility.

show abstract

“…Enhancing autophagy after TBI may weaken the expressions of neuronal apoptosis-related downstream molecules, including cleaved caspase-3, Bcl-2, and Bax, resulting in the dissociation of the Bcl-2/Beclin-1 complexes (Tang et al, 2017 ). Therefore, identifying neuroprotective mechanisms that are involved in autophagy-mediated neuronal survival, particularly the interaction between microglial activation and autophagy, may provide novel therapeutic strategies for TBI (Lin et al, 2016 ; Vlahakis et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Valproic Acid Attenuates Traumatic Brain Injury-Induced Inflammation in Vivo: Involvement of Autophagy and the Nrf2/ARE Signaling Pathway

Chen

Wang

Zhou

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element (ARE). ARE is known to associate with the transcription factor NF-E2-related factor 2 (Nrf2), a transcription factor that is associated with histone deacetylases (HDACs). This pathway, known as the Nrf2/ARE pathway, is a critical antioxidative factor pathway that regulates the balance of oxygen free radicals and the inflammatory response, and is also related to autophagic activities. Although valproic acid (VPA) is known to inhibit HDACs, it is unclear whether VPA plays a role in the microglia-mediated neuroinflammatory response after TBI via regulating oxidative stress and autophagy induced by the Nrf2/ARE signaling pathway. In this study, we demonstrate that microglial activation, oxidative stress, autophagy, and the Nrf2/ARE signaling pathway play essential roles in secondary injury following TBI. Treatment with VPA alleviated TBI-induced secondary brain injury, including neurological deficits, cerebral edema, and neuronal apoptosis. Moreover, VPA treatment upregulated the occurrence of autophagy and Nrf2/ARE pathway activity after TBI, and there was an increase in H3, H4 histone acetylation levels, accompanied by decreased transcriptional activity of the HDAC3 promoter in cortical lesions. These results suggest that VPA-mediated up-regulation of autophagy and antioxidative responses are likely due to increased activation of Nrf2/ARE pathway, through direct inhibition of HDAC3. This inhibition further reduces TBI-induced microglial activation and the subsequent inflammatory response, ultimately leading to neuroprotection.

show abstract

Mitochondrial respiration links TOR complex 2 signaling to calcium regulation and autophagy

Cited by 13 publications

References 3 publications

Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43

Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43

Deterioration of mitochondrial biogenesis and degradation in the endometrium is a cause of subfertility in cows

Valproic Acid Attenuates Traumatic Brain Injury-Induced Inflammation in Vivo: Involvement of Autophagy and the Nrf2/ARE Signaling Pathway

Contact Info

Product

Resources

About