Parkin ubiquitinates mTOR to regulate mTORC1 activity under mitochondrial stress

Park, Dohyun; Lee, Mi Nam; Jeong, Heeyoon; Koh, Ara; Yang, Yong Ryoul; Suh, Pann‐Ghill; Ryu, Sung Ho

doi:10.1016/j.cellsig.2014.06.010

Cited by 18 publications

(13 citation statements)

References 41 publications

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“…The increase in S6 phosphorylation in response to Parkin overexpression in young muscles is in line with recent literature indicating that Parkin can ubiquitinate mTOR, a post‐translational modification known to increase mTOR activity (Park et al . ). The lack of impact of Parkin overexpression on S6 phosphorylation suggests that the mechanisms regulating hypertrophy in adult skeletal muscle differ from those involved in the attenuation of sarcopenia.…”

Section: Discussionmentioning

confidence: 97%

Parkin overexpression protects from ageing‐related loss of muscle mass and strength

Leduc‐Gaudet

Reynaud

Hussain

et al. 2019

The Journal of Physiology

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Key points Recent evidence suggests that impaired mitophagy, a process in charge of removing damaged/dysfunctional mitochondria and in part regulated by Parkin, could contribute to the ageing‐related loss of muscle mass and function. In the present study, we show that Parkin overexpression attenuates ageing‐related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects from ageing‐related increases in markers of oxidative stress, fibrosis and apoptosis. Our findings place Parkin as a potential therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance. Abstract The ageing‐related loss of muscle mass and strength, a process called sarcopenia, is one of the most deleterious hallmarks of ageing. Solid experimental evidence indicates that mitochondrial dysfunctions accumulate with ageing and are critical in the sarcopenic process. Recent findings suggest that mitophagy, the process in charge of the removal of damaged/dysfunctional mitochondria, is altered in aged muscle. Impaired mitophagy represents an attractive mechanism that could contribute to the accumulation of mitochondrial dysfunctions and sarcopenia. To test this hypothesis, we investigated the impact of Parkin overexpression in skeletal muscles of young and old mice. Parkin was overexpressed for 4 months in muscles of young (3 months) and late middle‐aged (18 months) mice using i.m. injections of adeno‐associated viruses. We show that Parkin overexpression increased muscle mass, fibre size and mitochondrial enzyme activities in both young and old muscles. In old mice, Parkin overexpression increased muscle strength, primordial germ cell‐1α content and mitochondrial density. Parkin overexpression also attenuated the ageing‐related increase in 4‐hydroxynonenal content (a marker of oxidative stress) and type I collagen content (a marker of fibrosis), as well as the number of terminal deoxynucleotidyl transferase dUTP nick‐end labelling‐positive myonuclei (a marker of apoptosis). Overall, our results indicate that Parkin overexpression attenuates sarcopenia and unexpectedly causes hypertrophy in adult muscles. They also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects against oxidative stress, fibrosis and apoptosis. These findings highlight that Parkin may be an attractive therapeutic target with respect to attenuating sarcopenia and improving skeletal muscle health and performance.

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Section: Discussionmentioning

confidence: 97%

Parkin overexpression protects from ageing‐related loss of muscle mass and strength

Leduc‐Gaudet

Reynaud

Hussain

et al. 2019

The Journal of Physiology

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“…It has also been shown that mTOR undergoes proteasomal degradation, since E3 ubiquitin ligase FBXW7 deletion leads to mTOR accumulation in mouse embryonic fibroblasts from Fbxw7-/cells [Mao et al, 2008;Fu et al, 2009]. E3 ubiquitin ligases, such as TRAF6 [Linares et al, 2013], Parkin [Park et al, 2014], and CUL-4B-DDB1 [Ghosh et al, 2008] had been demonstrated to associate with mTORC1 complex.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal pH Plays a Key Role in Regulation of mTOR Activity in Osteoclasts

Carraro‐Lacroix

Wang

et al. 2015

J. Cell. Biochem.

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Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth. It has been shown to play an important role in osteoclast differentiation, particularly at the earlier stages of osteoclastogenesis. mTOR activation and function, as part of mTORC1 complex, is dependent on lysosomal localization and the vacuolar H(+) -ATPase (V-ATPase) activity; however, the precise mechanism is still not well understood. Using primary mouse osteoclasts that are known to have higher lysosomal pH due to R740S mutation in the V-ATPase a3 subunit, we investigated the role of lysosomal pH in mTORC1 signaling. Our results demonstrated that +/R740S cells had increased basal mTOR protein levels and mTORC1 activity compared to +/+ osteoclasts, while mTOR gene expression was decreased. Treatment with lysosomal inhibitors chloroquine and ammonium chloride, compounds known to raise lysosomal pH, significantly increased mTOR protein levels in +/+ cells, confirming the importance of lysosomal pH in mTOR signaling. These results also suggested that mTOR could be degraded in the lysosome. To test this hypothesis, we cultured osteoclasts with chloroquine or proteasomal inhibitor MG132. Both chloroquine and MG132 increased mTOR and p-mTOR protein levels in +/+ osteoclasts, suggesting that mTOR undergoes both lysosomal and proteasomal degradation. Treatment with cycloheximide, an inhibitor of new protein synthesis, confirmed that mTOR is constitutively expressed and degraded. These results show that, in osteoclasts, the lysosome plays a key role not only in mTOR activation but also in its deactivation through protein degradation, representing a novel molecular mechanism of mTOR regulation.

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“…Non-thermal plasma exerts anti-tumor effect by inducing RNF126 mediated K48-linked polyubiquitination and degradation of mTOR [ 46 ]. However, when faced with mitochondrial stress, E3 ligase PARKIN targets mTOR for ubiquitination, which maintains mTORC1 activity instead of affecting mTOR stability, thereby enhancing cell survival [ 47 ]. DUB USP9X can negatively modulate mTOR function and mTORC1 activity without changing mTOR protein level [ 48 ].…”

Section: Ubiquitination and Metabolic Signaling Pathwaysmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

260

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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Parkin ubiquitinates mTOR to regulate mTORC1 activity under mitochondrial stress

Cited by 18 publications

References 41 publications

Parkin overexpression protects from ageing‐related loss of muscle mass and strength

Parkin overexpression protects from ageing‐related loss of muscle mass and strength

Lysosomal pH Plays a Key Role in Regulation of mTOR Activity in Osteoclasts

The role of ubiquitination and deubiquitination in cancer metabolism

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