Tmem63c is a potential pro-survival factor in angiotensin II-treated human podocytes

Eisenreich, Andreas; Orphal, Miriam; Böhme, Karen; Kreutz, Reinhold

doi:10.1016/j.lfs.2020.118175

Cited by 7 publications

(7 citation statements)

References 42 publications

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“… 47 identified Tmem63c as a candidate due to its position within the quantitative trait locus region in a strain of hypertensive rats considered to be a suitable model system for investigating the genetic basis of albuminuria. However, no sequence variants were identified in Tmem63c in hypertensive rats, 47 , 48 and TMEM63C expression is absent in human kidneys in the Genotype-Tissue Expression (GTEx) database. Here, we unequivocally identify disruption of TMEM63C function as a cause of neurological disease in humans, consistent with the high expression levels of the TMEM63 family of molecules in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Tábara

Al-Salmi

Maroofian

et al. 2022

Brain

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The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into ‘pure HSP’ in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and ‘complex HSP’ when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria–endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Tábara

Al-Salmi

Maroofian

et al. 2022

Brain

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“…2 ). It functions in osmolarity regulation and like ACE2, interacts with angiotensin II, possibly reducing damage to kidney podocytes ( Eisenreich et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Aa¹,

Cheng²,

Werren³

2021

PeerJ

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Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that “coevolve” with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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“…Ang II is known as a key mediator in the progression of CKD, which affects actin cytoskeleton remodelling and induces kidney cell apoptosis, and in CKD 6,32–34 . The production of ROS can impact various pathophysiological processes.…”

Section: Discussionmentioning

confidence: 99%

Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1‐Drp1 signalling pathway

Chen

Liang

et al. 2022

Cell Proliferation

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Objectives: Increasing evidence suggests that mitochondrial dysfunction is the key driver of angiotensin II (Ang II)-induced kidney injury. This study was designed to investigate whether Sirtuin 6 (Sirt6) could affect Ang II-induced mitochondrial damage and the potential mechanisms.Materials and Methods: Podocyte-specific Sirt6 knockout mice were infused with Ang II and cultured podocytes were stimulated with Ang II to evaluate the effects of Sirt6 on mitochondrial structure and function in podocytes. Immunofluorescence staining was used to detect protein expression and mitochondrial morphology in vitro. Electron microscopy was used to assess mitochondrial morphology in mice.Western blotting was used to quantify protein expression.Results: Mitochondrial fission and decreased Sirt6 expression were observed in podocytes from Ang II-infused mice. In Sirt6-deficient mice, Ang II infusion induced increased apoptosis and mitochondrial fragmentation in podocytes than that in Ang II-infused wild-type mice. In cultured human podocytes, Sirt6 knockdown exacerbated Ang II-induced mitochondrial fission, whereas Sirt6 overexpression ameliorated the Ang II-induced changes in the balance between mitochondrial fusion and fission.Functional studies revealed that Sirt6 deficiency exacerbated mitochondrial fission by promoting dynamin-related protein 1 (Drp1) phosphorylation. Furthermore, Sirt6 mediated Drp1 phosphorylation by promoting Rho-associated coiled coil-containing protein kinase 1 (ROCK1) expression. Conclusion:Our study has identified Sirt6 as a vital factor that protects against Ang II-induced mitochondrial fission and apoptosis in podocytes via the ROCK1-Drp1 signalling pathway. | INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the occurrence and progression of chronic kidney diseases (CKD). 1 Zhaowei Chen and Wei Liang contributed equally to this work.

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Tmem63c is a potential pro-survival factor in angiotensin II-treated human podocytes

Cited by 7 publications

References 42 publications

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1‐Drp1 signalling pathway

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