Starving Neurons Show Sex Difference in Autophagy

Abstract

Sex-dependent differences in adaptation to famine have long been appreciated, thought to hinge on female versus male preferences for fat versus protein sources, respectively. However, whether these differences can be reduced to neurons, independent of typical nutrient depots, such as adipose tissue, skeletal muscle, and liver, was heretofore unknown. A vital adaptation to starvation is autophagy, a mechanism for recycling amino acids from organelles and proteins. Here we show that segregated neurons from males in culture are more vulnerable to starvation than neurons from females. Nutrient deprivation decreased mitochondrial respiration, increased autophagosome formation, and produced cell death more profoundly in neurons from males versus females. Starvation-induced neuronal death was attenuated by 3-methyladenine, an inhibitor of autophagy; Atg7 knockdown using small interfering RNA; or L-carnitine, essential for transport of fatty acids into mitochondria, all more effective in neurons from males versus females. Relative tolerance to nutrient deprivation in neurons from females was associated with a marked increase in triglyceride and free fatty acid content and a cytosolic phospholipase A2-dependent increase in formation of lipid droplets. Similar sex differences in sensitivity to nutrient deprivation were seen in fibroblasts. However, although inhibition of autophagy using Atg7 small interfering RNA inhibited cell death during starvation in neurons, it increased cell death in fibroblasts, implying that the role of autophagy during starvation is both sex- and tissue-dependent. Thus, during starvation, neurons from males more readily undergo autophagy and die, whereas neurons from females mobilize fatty acids, accumulate triglycerides, form lipid droplets, and survive longer.

JNK and Ceramide Kinase Govern the Biogenesis of Lipid Droplets through Activation of Group IVA Phospholipase A2

“…This mechanism is in keeping with our observation that okadaic acid induces LD biogenesis in a JNK-and cPLA 2 ␣-dependent fashion. 6 Regardless of the mechanism, our results clearly point to CERK as a potential target for the treatment of metabolic diseases.…”

“…This also stands probably for oleate-induced LD. 6 A literature survey shows that the identity of the MAPK cascade leading to the phosphorylation of cPLA 2 ␣ at Ser-505 is a matter of cell type and triggering stimulus, often involving ERK or/and p38 MAPK. However, to our knowledge only two recent reports have uncovered a key role of JNK in cPLA 2 ␣ activation, both related to the microbicidal activity of phagocytes.…”

“…In the last few years, the biology of LD has received increasing interest, due to the close relationship between an excess of lipid storage in certain tissues and pathologies such as obesity, diabetes, or atherosclerosis (3)(4)(5). Cellular stress has been related to the generation of LD, which might play a cytoprotective role (6,7). Therefore, dissecting the signaling pathways leading to LD formation may have important clinical applications in metabolic diseases and also in neurodegenerative diseases such as Parkinson and Alzheimer disease (8,9).…”

Lipid Droplet Biogenesis Induced by Stress Involves Triacylglycerol Synthesis That Depends on Group VIA Phospholipase A2

“…This mechanism has received most attention over the past years (1), but all tissues and cells types must be able to release fatty acids from TAG packed in LD (54), conceivably to supply local energetic needs through ␤-oxidation. In this regard, a recent report (55) shows that neurons from female rats form LD and survive nutrient deprivation better than neurons from male animals, which undergo autophagic death. Our results agree essentially with this report, suggesting that LD biogenesis in cells under stress may represent a lipid counterpart of autophagy: fatty acids used for structural functions (membrane phospholipids) could be reused for TAG synthesis in a process mediated by iPLA 2 -VIA and packed in LD for energetic functions in a process requiring cPLA 2 ␣.…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…В работе на культуре тканей было показано, что ингибирование нейрональной синтетазы оксида азота (Neuronal nitric oxide synthase, nNOS) редуцировало повреждение у сам-цов, но не у самок [43]. В следующем экспериментальном исследовании американских ученых продемонстрирова-но, что мужские нейроны более чувствительны к окси-дантному стрессу и глутаминовой эксайтотоксичности, а женские -к агентам, которые активируют каспаза-зависимый апоптоз [44]. Мужские нейроны погибали преимущественно путем активации AIF-зависимого пути, в то время как женские -преимущественно путем высвобождения цитохрома С из митохондрий с последу-ющей активацией каспазы.…”