Oncogenic Kinase Modulation of Mitochondrial Metabolism in Cancer Cells

Cancer cells often rewire energy production to support rapid proliferation, survival and metastasis. A central mechanism involves oncogenic protein kinases that directly or indirectly alter mitochondrial function. By phosphorylating key metabolic enzymes or mitochondrial transporters, these kinases shift the balance between glycolysis, oxidative phosphorylation and biosynthetic pathways. For example, phosphorylation of hexokinase by activated non-receptor tyrosine kinases enhances its mitochondrial association and catalytic efficiency, favouring rapid glucose utilisation. Tyrosine phosphorylation of the pyruvate dehydrogenase complex restrains flux into the tricarboxylic acid cycle, reinforcing aerobic glycolysis and limiting reactive oxygen species generation. In addition, kinases localised within mitochondria can modulate electron transport chain complexes, mitochondrial DNA maintenance and membrane potential to fine-tune respiratory activity and coordinate apoptosis. This intricate regulation contributes to metabolic plasticity and underpins therapy resistance, highlighting kinase-driven mitochondrial modulation as a promising target for anticancer intervention.

Research from Nature Portfolio

Foundational work has demonstrated that the prototypical Src kinase interacts with and phosphorylates mitochondrial hexokinase isoforms, markedly increasing their activity and enhancing glycolytic flux. Mutation of key phosphorylation sites on hexokinase attenuates glucose utilisation, cell proliferation and metastatic potential. These insights have cemented the role of Src family kinases in coupling oncogenic signalling to metabolic reprogramming at the mitochondrial interface, opening avenues for targeted inhibition.

Oncogenic Kinase Modulation of Mitochondrial Metabolism in Cancer Cells publication trend

The graph below shows the total number of articles in oncogenic kinase modulation of mitochondrial metabolism in cancer cells across all publications each year (not limited to Nature Index journals).

Technical terms

Oncogenic kinase: Enzyme that adds phosphate groups to proteins, driving cancer-promoting signalling.

Mitochondrial metabolism: Cellular processes within mitochondria that generate ATP and regulate redox balance.

Hexokinase: Enzyme catalysing the first step of glycolysis, often bound to the mitochondrial outer membrane.

Pyruvate dehydrogenase complex: Mitochondrial enzyme assembly converting pyruvate into acetyl-CoA for the tricarboxylic acid cycle.

Oxidative phosphorylation: Electron transport chain–driven synthesis of ATP using oxygen as the terminal electron acceptor.

Warburg effect: Preference of cancer cells for aerobic glycolysis over mitochondrial respiration, even in the presence of oxygen.

References

1. c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis. Nature Communications (2017).
2. Src: coordinating metabolism in cancer. Oncogene (2022).
3. Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation. Oncotarget (2016).
4. Intramitochondrial Src kinase links mitochondrial dysfunctions and aggressiveness of breast cancer cells. Cell Death & Disease (2019).