Abstract
ABSTRACTBoth 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-induced tumor-like growth, because knockdown of pdsw (also known as nd-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-induced tumor-like growth only when ROS scavengers are co-expressed. Together, 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.This article has an associated First Person interview with the first author of the paper.
Highlights
In the 1920s, Otto Warburg observed that cancer cells take up glucose and produce lactate vigorously even in the presence of oxygen, a phenomenon termed the Warburg effect or aerobic glycolysis (Warburg et al, 1927)
Mass and membrane potential (Δψm), we show that Homeodomain-interacting protein kinase (Hipk) tumorlike cells abound with hyperfused and hyperpolarized mitochondria, and that this metabolic shift depends on Myc upregulation
Given that mitochondrial metabolism can be influenced by alterations in energy demand and nutrient supply (Liesa and Shirihai, 2013; Spurlock et al, 2019), we were motivated to examine whether elevated Hipk leads to any changes in mitochondrial dynamics, abundance and energetics
Summary
In the 1920s, Otto Warburg observed that cancer cells take up glucose and produce lactate vigorously even in the presence of oxygen, a phenomenon termed the Warburg effect or aerobic glycolysis (Warburg et al, 1927). Warburg hypothesized that mitochondrial dysfunction is a cause of aerobic glycolysis and cancers (Warburg, 1956), which remains highly debated today. In support of this hypothesis, succinate dehydrogenase (SDH) and fumarase, which are mitochondrial enzymes of the tricarboxylic. Cancer mitochondrial metabolism is more heterogeneous than previously thought, and there is a need for an effective model system to aid in devising therapeutic strategies targeting mitochondria
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