UCLA study links fasting to mitochondrial splitting and mTORC2 Activation (UCLA)

Other studies have suggested that increasing mTORC2 can help improve lifespan… and this suggests perhaps why we don’t want to take high regular (daily) dosing of rapamycin, which eventually starts to suppress mTORC2. Perhaps this new research is also a rationale for periodic fasting for those taking rapamycin - it boosts mTORC2…

UCLA researchers found that fasting increases the splitting of mitochondria, which may have implications for metabolic and aging-related diseases.

In the study published in June, scientists examined the livers of mice that had been starved and identified the activated proteins, said Nuria Martinez-Lopez, the paper’s first author. They found that proteins in the mTORC2 cellular signaling pathway – known to be related to cell growth and metabolism – were activated by fasting, she added.

These proteins increased the splitting of the mitochondria during fasting, which might allow cells to more efficiently burn fatty acids to cope with starvation, said Rajat Singh, the paper’s corresponding author.

Going forward, the lab will investigate how activation of the mTORC2 pathway delays diseases and extends lifespan, Mattar said in the emailed statement.

“We could ambition a lower aging-disease burden, a scenario where we all can age healthily to enjoy our life until the last days,” she said in the statement.s

Full writeup:

Open Access Paper:

mTORC2–NDRG1–CDC42 axis couples fasting to mitochondrial fission

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, Rictor KO, NDRG1Ser336Ala mutants and Cdc42 -deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.