A Cellular Mechanism to Detect and Alleviate Reductive Stress

Manford, Andrew G.; Rodríguez-Pérez, Fernando; Shih, Karen Y.; Shi, Zhuo; Berdan, Charles A.; Choe, Mangyu; Titov, Denis V.; Nomura, Daniel K.; Rapé, Michael

doi:10.1016/j.cell.2020.08.034

Cited by 113 publications

(133 citation statements)

References 103 publications

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“…In addition, our data suggest that FNIP1 could not only regulate mitochondria biogenesis, but also regulate mitochondrial quality. Consistent with this notion, recent study also showed that FNIP1 regulate mitochondrial redox homeostasis [45].…”

Section: Plos Geneticsmentioning

confidence: 56%

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

et al. 2021

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Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.

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Section: Plos Geneticsmentioning

confidence: 56%

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

et al. 2021

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“…FLCN/FNIP complex may also play an important role in myoblast differentiation. A recent study identified FNIP1 as a key regulator of myoblast redox homeostasis and integrity (Manford et al, 2020). Under reductive stress, E3 ubiquitin ligase CUL FEM1B binds to reduced cysteines in FNIP1 and induces its degradation by the proteasome.…”

Section: Flcn/mtorc1/tfe3 In Stem Cellsmentioning

confidence: 99%

Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways

Reyes

Cuesta

Pause

2021

Front. Cell Dev. Biol.

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Folliculin (FLCN) is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.

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“…NRF2 can be regulated by targeting reactive cysteine residues in its E3, CUL3 KEAP1 (Zhang et al, 2004), using compounds, such as dimethyl fumarate, which has been approved for the treatment of multiple sclerosis (Dodson et al, 2019). However, inhibition of NRF2 has to be carefully monitored, as persistent stabilization of this transcription factor induces a gene expression program that triggers reductive stress and prevents muscle stem cell differentiation (Manford et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin‐dependent regulation of transcription in development and disease

Mark

Rapé

2021

EMBO Reports

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Transcription is an elaborate process that is required to establish and maintain the identity of the more than two hundred cell types of a metazoan organism. Strict regulation of gene expression is therefore vital for tissue formation and homeostasis. An accumulating body of work found that ubiquitylation of histones, transcription factors, or RNA polymerase II is crucial for ensuring that transcription occurs at the right time and place during development. Here, we will review principles of ubiquitin‐dependent control of gene expression and discuss how breakdown of these regulatory circuits leads to a wide array of human diseases.

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A Cellular Mechanism to Detect and Alleviate Reductive Stress

Cited by 113 publications

References 103 publications

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways

Ubiquitin‐dependent regulation of transcription in development and disease

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