MYC—an emerging player in mitochondrial diseases

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Juha Klefström¹  Jukka Kallijärvi²  Janne Purhonen² 

[1] Finnish Cancer Institute, FICAN South Helsinki University Hospital, Helsinki, Finland;Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland;Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, United States;Folkhälsan Research Center, Helsinki, Finland;Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland;

关键词: electron transport chain;    oxidative phosphorylation;    respiratory complex III;    mitochondrial integrated stress response;    Warburg effect;    cellular senescence;   

DOI  :  10.3389/fcell.2023.1257651

 received in 2023-07-12, accepted in 2023-08-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.

【 授权许可】

Unknown   
Copyright © 2023 Purhonen, Klefström and Kallijärvi.