Author response: A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model

Wong, Kenneth Kin Lam; Liao, Jenny Zhe; Verheyen, Esther M.

doi:10.7554/elife.46315.026

Cited by 2 publications

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Metabolic rewiring in fat-depletedDrosophilareveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism

Ugrankar-Banerjee,

Tran,

Bowerman

et al. 2024

Preprint

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Tissues store excess nutrients as triglyceride (TG) or glycogen, but how these reserves are sensed and communicate remains poorly understood. Here we identify molecular players orchestrating this metabolic balance, and uncover a signaling molecule that mediates energy homeostasis during fat depletion. We show tissue-specific depletion of fatty acyl-CoA synthase FASN1 in the Drosophila fat body (FB) causes near complete fat loss and metabolic remodeling that dramatically elevates carbohydrate metabolism, leading to a striking ~20-fold increase in glycogen storage. Proteomics and metabolomics identify key factors necessary for rewiring including glycolysis enzymes and target-of-brain-insulin (tobi). FASN1-deficient flies are viable but starvation sensitive, oxidatively stressed, and infertile. We also identify CG10824/cDIP as upregulated in FASN1-depleted Drosophila. cDIP is a leucine-rich-repeat protein with homology to secreted adipokines that fine-tune energy signaling. We find FB-specific cDIP loss promotes Drosophila adult obesity, and is required for development in the absence of FASN1-dependent lipid storage. Collectively, we show fat-depleted Drosophila rewire their metabolism to complete development, and identify cDIP as a putative new cytokine that signals fat insufficiency and may regulate energy homeostasis.

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Metabolic rewiring in fat-depletedDrosophilareveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism

Ugrankar-Banerjee,

Tran,

Bowerman

et al. 2024

Preprint

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Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

Wong

Liao

Shih

et al. 2020

Journal of Cell Science

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Both functional and dysfunctional mitochondria are known to underlie tumor progression. Here, we establish use of the proto-oncogene Drosophila Homeodomain-interacting protein kinase (Hipk) as a new tool to address this paradox. We find that, in Hipk-overexpressing tumor-like cells, mitochondria accumulate and switch from fragmented to highly fused interconnected morphologies. Moreover, elevated Hipk promotes mitochondrial membrane hyperpolarization. These mitochondrial changes are at least in part driven by the upregulation of Myc. Furthermore, we show that the altered mitochondrial energetics, but not morphology, is required for Hipk tumor-like growth as knockdown of pdsw (NDUFB10 in mammals; a Complex I subunit) abrogates the growth. Knockdown of ATPsynβ (a Complex V subunit), which produces higher levels of reactive oxygen species (ROS) than pdsw knockdown, instead synergizes with Hipk to potentiate JNK activation and the downstream induction of Matrix metalloproteinases. Accordingly, ATPsynβ knockdown suppresses Hipk tumor-like growth only when ROS scavengers are co-expressed. Altogether, our work presents an in vivo tumor model featuring the accumulation of hyperfused and hyperpolarized mitochondria, and reveals respiratory Complex subunit-dependent, opposing effects on tumorigenic outcomes.

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Author response: A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model

Cited by 2 publications

References 0 publications

Metabolic rewiring in fat-depletedDrosophilareveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism

Metabolic rewiring in fat-depletedDrosophilareveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism

Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth

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