Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation

Yang, Wanchun; Pang, Dejiang; Chen, Mina; Du, Chongyangzi; Jia, Lanlan; Wang, Luoling; He, Yun-Ling; Jiang, Wanxiang; Li, Luo; Yu, Zongyan; Mao, Mengqian; Yuan, Qiuyun; Tang, Ping; Xia, Xiaoqiang; Cui, Yiyuan; Jing, Bo; Platero, Alexander J.; Liu, Yan‐Hui; Wei, Yuquan; Worley, Paul F.; Xiao, Bo

doi:10.1016/j.devcel.2021.02.022

Cited by 31 publications

(23 citation statements)

References 86 publications

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“…Our findings indicate that TCA cycle and mitochondrial activity proteins are interacting with multiple ASD-risk genes, including genes that were not previously connected to metabolic processes. While, two ASD-risk genes (RHEB and BCKDK) have been previously implicated directly in metabolic processes 66, 106 . This highlights that our screen can identify relevant protein interactions and may even suggest a more direct connection between mitochondrial/metabolic processes and some genetic models (CDKL5 and KCTD13) 103, 105 .…”

Section: Mainmentioning

confidence: 99%

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

Murtaza

Cheng

Brown

et al. 2022

Preprint

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Autism spectrum disorder (ASD) is a genetically heterogeneous disorder. Sequencing studies have identified hundreds of risk genes for autism spectrum disorder (ASD), but the signaling networks of genes at the protein level remain largely unexplored, which can provide insight into previously unknown individual and convergent disease pathways in the brain. To address this gap, we used neuron-specific proximity-labeling proteomics (BioID) to identify protein-protein interaction (PPI) networks of 41 ASD-risk genes. Network analysis revealed the combined 41 risk gene PPI network map had more shared connectivity between unrelated ASD-risk genes than represented in existing public databases. We identified common pathways between established and uncharacterized risk genes, including synaptic transmission, mitochondrial/metabolic processes, Wnt signaling pathways, ion channel activity and MAPK signaling. Investigation of the mitochondrial and metabolic network using gene knockouts revealed a functional hub in neurons for multiple risk genes not previously associated with this pathway. Further, we identified that the uncharacterized ASD-risk gene PPP2R5D localizes to the synapse, which is disrupted by patient de novo missense mutations. Investigation of de novo missense variants of additional synaptic ASD-risk genes demonstrated that changes in PPI networks can capture synaptic transmission deficits. The neuronal 41 ASD-risk gene PPI network map also revealed enrichment for an additional 112 ASD-risk genes and human brain cell types implicated in ASD pathology. Interestingly, clustering of ASD-risk genes based on their PPI network connectivity identified multiple gene groups that correlate mutation-type to clinical behavior scores. Together, our data reveal that using PPI networks to map ASD risk genes can identify previously unknown individual and convergent neuronal signaling networks, provide a method to assess the impact of patient variants, and reveal new biological insight into disease mechanisms.

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Section: Mainmentioning

confidence: 99%

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

Murtaza

Cheng

Brown

et al. 2022

Preprint

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“…Cardiolipin exposure to the outer membrane not only affects mitophagy but also modulates α -synuclein aggregation and affects the electron transport in PD [ 45 ]. In contrast to the above pathways, Rheb is mainly located in the OMM and matrix, which regulates mitophagy related to energy state and ensures the efficiency of mitochondrial energy production [ 46 – 48 ]. Our group has recently revealed that Rheb is recruited to damage mitochondria for their engulfment within mitophagosomes in the axons of neurons, and such a mechanism promotes mitophagic removal of stressed mitochondria from distal axons to maintain mitochondrial homeostasis [ 49 , 50 ].…”

Section: The Mitophagy Pathways In Tbimentioning

confidence: 99%

Mitophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

Zhu

Huang

Shan

et al. 2022

Oxidative Medicine and Cellular Longevity

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Traumatic brain injury (TBI) contributes to death, and disability worldwide more than any other traumatic insult and damage to cellular components including mitochondria leads to the impairment of cellular functions and brain function. In neurons, mitophagy, autophagy-mediated degradation of damaged mitochondria, is a key process in cellular quality control including mitochondrial homeostasis and energy supply and plays a fundamental role in neuronal survival and health. Conversely, defective mitophagy leads to the accumulation of damaged mitochondria and cellular dysfunction, contributing to inflammation, oxidative stress, and neuronal cell death. Therefore, an extensive characterization of mitophagy-related protective mechanisms, taking into account the complex mechanisms by which each molecular player is connected to the others, may provide a rationale for the development of new therapeutic strategies in TBI patients. Here, we discuss the contribution of defective mitophagy in TBI, and the underlying molecular mechanisms of mitophagy in inflammation, oxidative stress, and neuronal cell death highlight novel therapeutics based on newly discovered mitophagy-inducing strategies.

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“…Our recent work identifies Rheb (a Ras-like GTPase) as a general activator of mitochondrial PDH activity of multiple cell types, including neurons, neuroglia, and hepatocytes, with implications to cellular ATP production ( Jia et al, 2021 ; Yang et al, 2021 ). Rheb is a small GTPase that functions as a direct and essential activator of mTORC1, a kinase complex that functions as a master regulator of cellular metabolism ( Saxton and Sabatini 2017 ), growth, and differentiation ( Delgoffe et al, 2011 ; Zou et al, 2011 ; Zou et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, the role of Rheb in activating PDH-mediated mitochondrial activity is independent of its role in activating mTORC1. In response to metabolic needs, Rheb is translocated into the mitochondrial matrix, where it binds PDH phosphatases (PDP1 and PDP2) and stabilizes the phosphatase activity toward PDH and thus keep PDH in the active state ( Yang et al, 2021 ). The effect of Rheb on PDH activity is not related to its capacity of activating mTORC1, but the relative amount of Rheb protein is more relevant ( Yang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…In response to metabolic needs, Rheb is translocated into the mitochondrial matrix, where it binds PDH phosphatases (PDP1 and PDP2) and stabilizes the phosphatase activity toward PDH and thus keep PDH in the active state ( Yang et al, 2021 ). The effect of Rheb on PDH activity is not related to its capacity of activating mTORC1, but the relative amount of Rheb protein is more relevant ( Yang et al, 2021 ). All these findings suggest that Rheb could regulate hepatic lipid metabolism/homeostasis through mTORC1-dependenet and -independent mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver

Yang

et al. 2022

Front. Cell Dev. Biol.

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Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.

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Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation

Cited by 31 publications

References 86 publications

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

Mitophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver

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