Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

Feng, Li; Wang, Yunyue; Zeller, Karen; Potter, James J.; Wonsey, Diane R.; O’Donnell, Kathryn A.; Kim, Jung-whan; Yustein, Jason T.; Lee, Linda A.; Dang, Chi V.

doi:10.1128/mcb.25.14.6225-6234.2005

Cited by 535 publications

(519 citation statements)

References 49 publications

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“…The depletion of mitochondrial function has recently been shown to induce MYC overexpression, and we also observed a substantial upregulation of MYC in cells bearing mtDNA deletions [40,[44][45][46][47]62] …”

Section: Single Mtdna Deletions Produce Inhibition Of Multiple Mitochsupporting

confidence: 73%

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Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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Section: Single Mtdna Deletions Produce Inhibition Of Multiple Mitochsupporting

confidence: 73%

“…MYC, which has recently been shown to serve as a transcription factor for mitochondrial biogenesis, responds to mitochondrial functional depletion [40,[44][45][46][47].…”

Section: Mtdna Deletions Activate Snare Genes Stress Genes Myc Andmentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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“…Since both mTORC1 and MYC are known to increase mitochondrial respiration (Li et al , 2005; Cunningham et al , 2007), we examined mitochondrial respiration and ROS production in the cellular BL model. TSC1 knockdown in P493‐6 cells increased total oxygen consumption as well as the ratio of oxygen consumption over lactate production (as determined by acidification), which was measured with the Seahorse XF extracellular flux analyzer (Fig 4A, left graph and Fig EV4B).…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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“…In cancer, pathological activation of MYC commonly plays a key role in disease pathogenesis. MYC stimulates expression of many mitochondrial genes that are encoded in the nucleus and even regulates mitochondrial biogenesis itself (Li et al, 2005). In the Connectivity Map, an MTH FD2 knockdown signature recapitulated changes in expression associated with knockdown of MYC.…”

Section: Discussionmentioning

confidence: 99%

Targeting MTHFD2 in acute myeloid leukemia

Pikman¹,

Puissant²,

Alexe³

et al. 2016

J Cell Biol

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Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

Cited by 535 publications

References 49 publications

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Targeting MTHFD2 in acute myeloid leukemia

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