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TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of

Surbhi Chouhan1,2, Mithila Sawant1,2, Cody Weimholt3

  • 1Department of Surgery, Cancer Research Building, St. Louis, MO, USA.

Autophagy
|July 27, 2022
PubMed

Insights

Cancer cells exploit tyrosine kinase TNK2/ACK1 to boost mitochondrial energy production by phosphorylating ATP synthase. Inhibiting TNK2 triggers mitophagy, reducing tumor growth and offering a new cancer therapy strategy.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Mitochondrial Metabolism

Background:

  • Cancer cells require high energy due to rapid macromolecular synthesis, necessitating metabolic adaptations.
  • Oncogenic tyrosine kinases are activated in cancer, but their direct role in meeting cancer cell mitochondrial energy demands is unclear.
  • Mitochondrial function and metabolic reprogramming are critical for cancer cell survival and proliferation.

Purpose of the Study:

  • To elucidate the mechanism by which tyrosine kinase activity directly enhances mitochondrial energy output in cancer cells.
  • To investigate the role of TNK2/ACK1 in regulating ATP synthase stability and activity.
  • To evaluate the therapeutic potential of targeting TNK2 for cancer treatment, specifically inducing mitophagy.

Main Methods:

  • Phosphorylation analysis of ATP synthase F1 subunit alpha (ATP5F1A) by TNK2/ACK1.
  • Assessment of Complex V stability and mitochondrial energy output in cancer cells.
  • Treatment with a TNK2 inhibitor ((R)-9b) and evaluation of its effects on mitophagy, tumor growth, and p-Y-ATP5F1A levels.
  • Analysis of Tnk2 transgenic mice and human prostate cancer progression.

Main Results:

  • TNK2/ACK1 phosphorylates ATP5F1A at Tyr243 and Tyr246, increasing Complex V stability and mitochondrial energy output.
  • Phospho-ATP5F1A (p-Y-ATP5F1A) inhibits binding to ATP5IF1, sustaining mitochondrial activity and promoting cancer growth.
  • The TNK2 inhibitor (R)-9b reverses these effects, inducing mitophagy and reducing prostate tumor growth while sparing normal cells.
  • Depletion of p-Y-ATP5F1A is essential for (R)-9b-mediated mitophagy and tumor suppression.
  • Tnk2 overexpression in mice leads to increased p-Y-ATP5F1A, reduced mitophagy, and prostatic intraepithelial neoplasia (PINs).
  • Elevated p-Y-ATP5F1A correlates with prostate cancer progression.

Conclusions:

  • Tyrosine kinase-mediated regulation of mitochondrial energy production represents a vulnerability in cancer cells.
  • TNK2/ACK1 plays a crucial role in enhancing mitochondrial ATP production through ATP5F1A phosphorylation.
  • TNK2 inhibitors can function as 'mitocans,' selectively inducing mitophagy in cancer cells and offering a targeted therapeutic strategy.
Keywords:
ATP5F1AATP5IF1TNK2/ACK1mitochondrial dysfunctionmitochondrial vulnerabilitymitophagytyrosine phosphorylation

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