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Angiotensin II Regulates Mitochondrial mTOR Pathway Activity Dependent on Acyl-CoA Synthetase 4 in Adrenocortical

Katia E Helfenberger1,2, Giuliana F Argentino1,2, Yanina Benzo1,2

  • 1Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121ABG, Argentina.

Endocrinology
|October 18, 2022
PubMed

Insights

Angiotensin II activates mTORC1/2 signaling in adrenocortical cells via ACSL4, promoting proliferation. This study highlights ACSL4

Area of Science:

  • Cell Biology
  • Molecular Endocrinology
  • Cancer Signaling

Background:

  • Mammalian target of rapamycin complexes 1 and 2 (mTORC1/2) regulate critical cellular functions, including proliferation, and are often dysregulated in cancer.
  • Acyl-CoA synthetase type 4 (ACSL4) is a newly identified regulator of mTORC1/2, particularly in breast cancer and hormone-regulated steroidogenesis in adrenocortical cells.
  • mTORC1/2 signaling is vital for the proliferation of human adrenocortical tumor cells (H295R) and exhibits complex subcellular localization patterns.

Purpose of the Study:

  • To investigate the regulation of mTORC1/2 activation by angiotensin II (Ang II), the primary trophic hormone for adrenocortical cells.
  • To determine the subcellular localization of mTORC1/2 signaling proteins in response to Ang II.
  • To elucidate the role of ACSL4 in mediating Ang II-induced mTORC1/2 activation and its impact on H295R cell proliferation.

Main Methods:

  • Time-dependent analysis of mTORC1/2 pathway protein phosphorylation in H295R cells stimulated with Ang II.
  • Assessment of mitochondrial protein phosphorylation, including ribosomal protein S6, Akt, and Rictor.
  • Investigation of glycogen synthase kinase 3 (GSK3) phosphorylation and inactivation in mitochondria.
  • Comparative analysis of mTORC1/2 activation kinetics induced by Ang II versus epidermal growth factor (EGF).
  • Evaluation of ACSL4's necessity for Ang II-triggered mTORC1/2 effector phosphorylation and H295R cell proliferation.

Main Results:

  • Ang II time-dependently promoted the phosphorylation and activation of key mTORC1/2 pathway proteins, including mitochondrial ribosomal protein S6, Akt (at T308 and S473), and Rictor.
  • Ang II induced mitochondrial GSK3 phosphorylation and inactivation, which facilitates mTORC1 activation.
  • ACSL4 was found to be essential for the phosphorylation of mTORC1/2 effectors and Ang II-induced H295R cell proliferation.
  • Ang II activates mitochondrial mTORC1/2 signaling proteins through ACSL4, directly impacting adrenocortical cell proliferation.

Conclusions:

  • Angiotensin II is a potent activator of mTORC1/2 signaling in adrenocortical cells, with a significant role for mitochondrial localization.
  • ACSL4 is a critical mediator of Ang II-induced mTORC1/2 activation and subsequent proliferation of adrenocortical tumor cells.
  • Targeting the ACSL4-mTORC1/2 axis may represent a therapeutic strategy for adrenocortical tumors.
Keywords:
acyl-CoA synthetase type 4adrenocortical human cellsangiotensin IIcompartmentalizationmTORC proteinsmitochondria

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