Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Autophagy is a vital catabolic process for cell survival under stress, regulated by the target of rapamycin (TOR) kinase.
• TORC1 and TORC2 are distinct TOR complexes; TORC1 responds to nitrogen, while TORC2 positively regulates autophagy during amino acid starvation via Ypk1.
• TORC2-Ypk1 signaling impacts autophagy by repressing calcineurin and promoting the general amino acid control (GAAC) response, but the precise mechanism is unclear.

Purpose of the Study:

• To elucidate the mechanism by which TORC2-Ypk1 signaling regulates calcineurin activity in the context of autophagy.
• To identify the signaling intermediates connecting TORC2-Ypk1 to calcineurin activation.
• To understand the role of mitochondrial function and oxidative stress in this regulatory pathway.

Main Methods:

• Investigated TORC2-Ypk1 signaling in autophagy-deficient cells.
• Analyzed mitochondrial respiration and reactive oxygen species (ROS) production.
• Examined the role of the calcium channel regulatory protein Mid1 in calcineurin activation and the GAAC response.

Main Results:

• Activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulator.
• TORC2-Ypk1-deficient cells exhibit perturbed mitochondrial respiration, leading to increased mitochondrial ROS.
• Mitochondrial ROS signal to Mid1, activating calcineurin, which inhibits the GAAC response and autophagy.

Conclusions:

• A novel pathway regulating autophagy involves TORC2, mitochondrial oxidative stress, and calcium homeostasis.
• Mid1 acts as a crucial link between mitochondrial dysfunction, calcium signaling, and calcineurin-mediated inhibition of autophagy.
• This pathway highlights the intricate coordination of cellular stress responses for maintaining cell survival.