Starving neurons show sex difference in autophagy

Area of Science:

• Neuroscience
• Cell Biology
• Metabolism

Background:

• Sex-dependent differences in famine adaptation are known, but their basis in neurons independent of other tissues was unclear.
• Autophagy, a cellular recycling process, is crucial for adapting to starvation.

Purpose of the Study:

• To investigate sex-based differences in neuronal response to starvation.
• To determine if neuronal vulnerability to starvation is linked to autophagy and lipid metabolism.

Main Methods:

• Primary neuronal cultures from male and female mice were subjected to nutrient deprivation.
• Autophagy was assessed via autophagosome formation and Atg7 knockdown.
• Cell death, mitochondrial respiration, and lipid metabolism (triglycerides, fatty acids, lipid droplets) were measured.

Main Results:

• Male neurons showed increased vulnerability, cell death, and autophagosome formation under starvation compared to female neurons.
• Inhibition of autophagy or enhancement of fatty acid transport protected male neurons.
• Female neurons accumulated triglycerides and formed lipid droplets, correlating with greater starvation tolerance.

Conclusions:

• Neurons exhibit sex-specific responses to starvation, with males being more susceptible due to higher autophagy rates.
• Female neurons survive starvation longer by utilizing lipid reserves and forming lipid droplets.
• Autophagy's role in starvation is both sex- and tissue-dependent, as shown by contrasting neuronal and fibroblast responses.