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.

Apoptosis, or programmed cell death, is a physiological form of cell death that is important for normal embryologic development and cell turnover in adult organisms. Cumulative evidence suggests that apoptosis can also be triggered in tissues without a high rate of cell turnover, including those within the central nervous system (CNS). In fact, a crucial role for apoptosis in delayed neuronal loss after both acute and chronic CNS injury is emerging. In the current review we summarize the growing evidence that apoptosis occurs after traumatic brain injury (TBI), from experimental models to humans. This includes the identification of apoptosis after TBI, initiators of apoptosis, key modulators of apoptosis such as the Bcl-2 family, key executioners of apoptosis such as the caspase family, final pathways of apoptosis, and potential therapeutic interventions for blocking neuronal apoptosis after TBI.

Autophagy is a homeostatic process for recycling of proteins and organelles, induced by nutrient deprivation and regulated by oxygen radicals. Whether autophagy is induced after traumatic brain injury (TBI) is not established. We show that TBI in mice results in increased ultrastructural and biochemical evidence of autophagy. Specifically, autophagosomal vacuoles and secondary lysosomes were frequently observed in cell processes and axons in ipsilateral brain regions by electron microscopy, and lipidated microtubule-associated protein light chain 3, a biochemical footprint of autophagy referred to as LC3 II, was increased at 2 and 24 h after TBI versus controls. Since oxygen radicals are believed to be important in the pathogenesis of TBI and are essential for the process of starvation-induced autophagy in vitro, we also sought to determine if treatment with the antioxidant γ-glutamylcysteinyl ethyl ester (GCEE) reduced autophagy and influenced neurologic outcome after TBI in mice. Treatment with GCEE reduced oxidative stress and partially reduced LC3 II formation in injured brain at 24 h after TBI versus vehicle. Treatment with GCEE also led to partial improvement in behavioral and histologic outcome versus vehicle. Taken together, these data show that autophagy occurs after experimental TBI, and that oxidative stress contributes to overall neuropathology, in part by initiating or influencing autophagy.

Autophagy is a homeostatic process for recycling of proteins and organelles, that increases during times of nutrient deprivation and is regulated by reactive oxygen species. We reported that autoph...

J. Neurochem. (2008) 104, 1700–1711. Poly‐ADP‐ribosylation is a post‐translational modification performed by poly(ADP‐ribose) polymerases (PARP), involved in many diverse cellular functions including DNA repair, transcription, and long‐term potentiation. Paradoxically, PARP over‐activation under pathologic conditions including traumatic brain injury (TBI) results in cell death. We previously demonstrated that intra‐mitochondrial poly‐ADP‐ribosylation occurs following excitotoxic and oxidative injury in vitro. Here we sought to identify mitochondrial proteins modified by poly‐ADP‐ribosylation after TBI in vivo. Poly‐ADP‐ribosylation within mitochondria from injured brain after experimental TBI in rats was first verified using western blot and immuno‐electron microscopy. Poly‐ADP‐ribosylated mitochondrial proteins identified using a targeted proteomic approach included voltage‐dependent anion channel‐1, mitofilin, mitochondrial stress proteins, and the electron transport chain components F₁F₀ ATPase, cytochrome c oxidase, and cytochrome c reductase. To examine the functional consequences of mitochondrial poly‐ADP‐ribosylation, isolated rat brain mitochondria were exposed to conditions of nitrosative stress known to activate PARP. PARP activation‐induced reductions in State 3 respiration were prevented by the PARP‐1 inhibitor 5‐iodo‐6‐amino‐1,2‐benzopyrone or exogenous poly(ADP‐ribose) glycohydrolase. As the effects of PARP activation on mitochondrial respiration appear regulated by poly(ADP‐ribose) glycohydrolase, a direct effect of poly‐ADP‐ribosylation on electron transport chain function is suggested. These findings may be of relevance to TBI and other diseases where mitochondrial dysfunction occurs.