VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

Kim, Jeong‐Han; Gupta, Rajeev; Blanco, Luz P.; Yang, Shutong; Shteinfer‐Kuzmine, Anna; Wang, Kening; Zhu, Jun; Yoon, Hee Eun; Wang, Xinghao; Kerkhofs, Martijn; Kang, Hyeog; Brown, Alexandra L.; Park, Sung-Jun; Xu, Xihui; Rilland, Eddy Zandee van; Kim, Myung K.; Cohen, Jeffrey I.; Kaplan, Mariana J.; Shoshan‐Barmatz, Varda; Chung, Jay H.

doi:10.1126/science.aav4011

Cited by 380 publications

(416 citation statements)

References 35 publications

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“…Although the involvement of VDACs in the formation of the permeability transition pore has been debated ( 35 ), studies also indicate that adverse changes in the lipid profile of the OMM could trigger the observed VDAC oligomerization and release of mitochondrial DNA ( 36 ). The most significant change in the lipidome is the lowering of CL and a concomitant increase in PG content ( 23 , 27 , 28 ).…”

Section: Resultsmentioning

confidence: 99%

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

Srivastava

Mahalakshmi

2020

Journal of Biological Chemistry

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Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMM) are major channels of communication between the cytosol and mitochondria, and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd–stranded, i.e., 19-stranded structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel (VDAC). Here, using human VDAC as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V216, V217, V218) and larger (V220, V221) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid–dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage–gated channel regulation, efficient mitochondrial targeting and in vivo cell survival, with lipid–modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.

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Section: Resultsmentioning

confidence: 99%

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

Srivastava

Mahalakshmi

2020

Journal of Biological Chemistry

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“…This is possibly due to mtDNA release, though a direct role for mtDNA has not been rigorously assessed . An intriguing recent report suggests that cells experiencing mitochondrial stress caused by the lack of mitochondrial endonuclease G release mtDNA through pores formed by oligomers of the voltage‐dependent anion channel (VDAC) . As mitochondrial DNA release is thought to play a role in the pathogenesis of lupus , a role for VDAC pore formation was tested in an in vivo model of lupus‐like disease.…”

Section: Introductionmentioning

confidence: 99%

“…As mitochondrial DNA release is thought to play a role in the pathogenesis of lupus , a role for VDAC pore formation was tested in an in vivo model of lupus‐like disease. Using the VDAC1 oligomerisation inhibitor VBIT‐4, the authors were able to reduce lupus‐like symptoms in lupus‐prone mice, providing a rationale to target VDAC‐mediated mtDNA release in this disease .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA in inflammation and immunity

2020

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Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora of different pattern recognition receptors and innate immune responses, including cGAS‐STING, TLR9 and inflammasome formation leading to, among others, robust type I interferon responses. In this Review, we discuss how mtDNA can be released from the mitochondria, the various inflammatory pathways triggered by mtDNA release and its myriad biological consequences for health and disease.

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“…The protein is also involved in cholesterol transport and mediates the fluxes of ions, including cytosolic and Ca 2+ , as well as being involved in mitochondria-ER Ca 2+ signaling, serving as a ROS transporter, and regulating the redox states of mitochondria and the cytosol [40,42]. Furthermore, recently we demonstrated that VDAC1 oligomers mediate the release of mitochondrial DNA fragments [43]. Thus, VDAC1 appears to be a convergence point for a variety of cell survival and death signals, mediated through association with various ligands and proteins [40,42].The importance of VDAC1 in cell energy and metabolism homeostasis is reflected in its over-expression in many cancers [44,45], and with down-regulation resulting in reduced metabolite exchange between mitochondria and cytosol and inhibited cell and tumor growth [44,[46][47][48].…”

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confidence: 99%

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confidence: 99%

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

Amsalem

Arif

Shteinfer‐Kuzmine

et al. 2020

Cancers

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Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.Cancers 2020, 12, 1031 2 of 25 cellular metabolic activity regulates transcriptional networks and cell-fate decisions via epigenetic programs involving metabolite-dependent effects on chromatin organization. Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16].There is now an accumulation of evidence that the epigenome is sensitive to cellular metabolism and a link between metabolism and epigenetics [3][4][5][17][18][19] has been proposed, with epigenetics and gene transcription being influenced by products of metabolic pathways [...

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VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

Cited by 380 publications

References 35 publications

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

Mitochondrial DNA in inflammation and immunity

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

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