Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43.

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Stem Cell Differentiation

Background:

• Rictor is essential for mTORC2 signaling and Akt phosphorylation.
• Rictor knockdown impairs cardiomyocyte differentiation and electrophysiology.
• Rictor knockdown reduces connexin 43 (Cx43) expression, affecting mitochondrial Cx43 (mtCx43).

Purpose of the Study:

• To investigate the mechanisms of mitochondrial damage in Rictor-knockdown cardiomyocytes.
• To elucidate the role of mtCx43 in Rictor-mediated mitochondrial dysfunction.

Main Methods:

• Utilized mouse embryonic stem (ES) cell differentiation model.
• Performed transmission electron microscopy to assess mitochondrial morphology.
• Measured ATP production, mitochondrial membrane potential, and respiratory chain complex activity.
• Investigated Cx43 translocation, mTOR/Akt signaling, HDAC6 expression, and Hsp90 acetylation.

Main Results:

• Rictor knockdown caused mitochondrial swelling and rupture.
• Decreased ATP production, mitochondrial transmembrane potential, and respiratory chain activity were observed.
• Cx43 translocation into mitochondria was inhibited.
• mTOR/Akt pathway inactivation led to reduced HDAC6, increased Hsp90 acetylation, and impaired Hsp90-Cx43-TOM20 complex formation.

Conclusions:

• Mitochondrial Cx43 is crucial in Rictor knockdown-induced mitochondrial damage.
• Rictor regulates mitochondrial function via the mTOR/Akt/HDAC6/Hsp90 pathway affecting mtCx43.
• Targeting Rictor or its downstream effectors may offer therapeutic strategies for cardiac mitochondrial dysfunction.