GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.

In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions of these vesicles and potentially associated proteins remain unknown. GOLPH3, a PI(4)P-interacting GA protein, is elevated in various types of solid tumors, including breast cancer, yet its precise role is unclear. Interestingly, GOLPH3 levels influence mitochondrial mass by affecting cardiolipin synthesis, an exclusive mitochondrial lipid. However, the mechanism by which GOLPH3 influences mitochondria is not fully understood. Our live-cell imaging analysis showed GFP-GOLPH3 associating with PI(4)P vesicles colocalizing with YFP-DRP1 at mitochondrial fission sites. We tested the functional significance of these observations with GOLPH3 knockout in MDA-MB-231 cells of breast cancer, resulting in a fragmented mitochondrial network and reduced bioenergetic function, including decreased mitochondrial ATP production, mitochondrial membrane potential, and oxygen consumption. Our findings suggest a potential negative regulatory role for GOLPH3 in mitochondrial fission, impacting mitochondrial function and providing insights into GA-mitochondria communication.

Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease.

Social interactions have a significant impact on health in humans and animal models. Social isolation initiates a cascade of stress-related physiological disorders and stands as a significant risk factor for a wide spectrum of morbidity and mortality. Indeed, social isolation stress (SIS) is indicative of cognitive decline and risk to neurodegenerative conditions, including Alzheimer's disease (AD). This study aimed to evaluate the impact of chronic, long-term SIS on the propensity to develop hallmarks of AD in young degus (Octodon degus), a long-lived animal model that mimics sporadic AD naturally. We examined inflammatory factors, bioenergetic status, reactive oxygen species (ROS), oxidative stress, antioxidants, abnormal proteins, tau protein, and amyloid-ß (Aß) levels in the hippocampus of female and male degus that were socially isolated from post-natal and post-weaning until adulthood. Additionally, we explored the effect of re-socialization following chronic isolation on these protein profiles. Our results showed that SIS promotes a pro-inflammatory scenario more severe in males, a response that was partially mitigated by a period of re-socialization. In addition, ATP levels, ROS, and markers of oxidative stress are severely affected in female degus, where a period of re-socialization fails to restore them as it does in males. In females, these effects might be linked to antioxidant enzymes like catalase, which experience a decline across all SIS treatments without recovery during re-socialization. Although in males, a previous enzyme in antioxidant pathway diminishes in all treatments, catalase rebounds during re-socialization. Notably, males have less mature neurons after chronic isolation, whereas phosphorylated tau and all detectable forms of Aß increased in both sexes, persisting even post re-socialization. Collectively, these findings suggest that long-term SIS may render males more susceptible to inflammatory states, while females are predisposed to oxidative states. In both scenarios, the accumulation of tau and Aß proteins increase the individual susceptibility to early-onset neurodegenerative conditions such as AD.

Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice.

Aging is a physiological process that generates progressive decline in many cellular functions. There are many theories of aging, and one of great importance in recent years is the mitochondrial theory of aging, in which mitochondrial dysfunction that occurs at advanced age could be responsible for the aged phenotype. In this context, there is diverse information about mitochondrial dysfunction in aging, in different models and different organs. Specifically, in the brain, different studies have shown mitochondrial dysfunction mainly in the cortex; however, until now, no study has shown all the defects in hippocampal mitochondria in aged female C57BL/6J mice. We performed a complete analysis of mitochondrial function in 3-month-old and 20-month-old (mo) female C57BL/6J mice, specifically in the hippocampus of these animals. We observed an impairment in bioenergetic function, indicated by a decrease in mitochondrial membrane potential, O2 consumption, and mitochondrial ATP production. Additionally, there was an increase in ROS production in the aged hippocampus, leading to the activation of antioxidant signaling, specifically the Nrf2 pathway. It was also observed that aged animals had deregulation of calcium homeostasis, with more sensitive mitochondria to calcium overload and deregulation of proteins related to mitochondrial dynamics and quality control processes. Finally, we observed a decrease in mitochondrial biogenesis with a decrease in mitochondrial mass and deregulation of mitophagy. These results show that during the aging process, damaged mitochondria accumulate, which could contribute to or be responsible for the aging phenotype and age-related disabilities.

Age-Dependent Behavioral and Synaptic Dysfunction Impairment Are Improved with Long-Term Andrographolide Administration in Long-Lived Female Degus (Octodon degus).

In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.

How Many Sirtuin Genes Are Out There? Evolution of Sirtuin Genes in Vertebrates With a Description of a New Family Member.

Studying the evolutionary history of gene families is a challenging and exciting task with a wide range of implications. In addition to exploring fundamental questions about the origin and evolution of genes, disentangling their evolution is also critical to those who do functional/structural studies to allow a deeper and more precise interpretation of their results in an evolutionary context. The sirtuin gene family is a group of genes that are involved in a variety of biological functions mostly related to aging. Their duplicative history is an open question, as well as the definition of the repertoire of sirtuin genes among vertebrates. Our results show a well-resolved phylogeny that represents an improvement in our understanding of the duplicative history of the sirtuin gene family. We identified a new sirtuin gene family member (SIRT3.2) that was apparently lost in the last common ancestor of amniotes but retained in all other groups of jawed vertebrates. According to our experimental analyses, elephant shark SIRT3.2 protein is located in mitochondria, the overexpression of which leads to an increase in cellular levels of ATP. Moreover, in vitro analysis demonstrated that it has deacetylase activity being modulated in a similar way to mammalian SIRT3. Our results indicate that there are at least eight sirtuin paralogs among vertebrates and that all of them can be traced back to the last common ancestor of the group that existed between 676 and 615 millions of years ago.

Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.

During normal aging, there is a decline in all physiological functions in the organism. One of the most affected organs is the brain, where neurons lose their proper synaptic function leading to cognitive impairment. Aging is one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer's disease. One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates. The most studied brain aggregates are the senile plaques, formed by Aß peptide; however, the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity. It is reported that neurons undergo severe mitochondrial dysfunction with age, with a decrease in adenosine 5'-triphosphate production, loss of the mitochondrial membrane potential, redox imbalance, impaired mitophagy, and loss of calcium buffer capacity. Interestingly, abnormal tau protein interacts with several mitochondrial proteins, suggesting that it could induce mitochondrial dysfunction. Nevertheless, whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown. A recent study of our laboratory shows that phosphorylated tau at Ser396/404 (known as PHF-1), an epitope commonly related to pathology, accumulates inside mitochondria during normal aging. This accumulation occurs preferentially in synaptic mitochondria, which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals. Here, we review the main tau modifications promoting mitochondrial dysfunction, and the possible mechanism involved. Also, we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging. Finally, we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer's disease, which could be considered as an early event in the neurodegenerative process. Thus, phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.

Synaptic Mitochondria: An Early Target of Amyloid-ß and Tau in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-ß (Aß) peptide. The amyloid hypothesis proposes that Aß accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aß-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aß accumulation or if is a consequence of it. Aß promotes mitochondrial failure. However, amyloid ß precursor protein (AßPP) could be cleaved in the mitochondria producing Aß peptide. Mitochondrial-produced Aß could interact with newly formed ones or with Aß that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aß toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.

WNT Signaling Is a Key Player in Alzheimer's Disease.

The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized ß-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/ß-catenin signaling activation exerts a neuroprotective mechanism against the amyloid ß (Αß) peptide toxicity. Later, we found that WNT/ß-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/ß-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/ß-catenin dysfunction results in Aß production and aggregation. We highlight the importance of WNT/ß-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/ß-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.

Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice.

Brain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.

Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics.

High-fat diet (HFD)-induced obesity is associated with increased cancer risk. Long-term feeding with HFD increases the concentration of the saturated fatty acid palmitic acid (PA) in the hypothalamus. We previously showed that, in hypothalamic neuronal cells, exposure to PA inhibits the autophagic flux, which is the whole autophagic process from the synthesis of the autophagosomes, up to their lysosomal fusion and degradation. However, the mechanism by which PA impairs autophagy in hypothalamic neurons remains unknown. Here, we show that PA-mediated reduction of the autophagic flux is not caused by lysosomal dysfunction, as PA treatment does not impair lysosomal pH or the activity of cathepsin B.Instead, PA dysregulates autophagy by reducing autophagosome-lysosome fusion, which correlates with the swelling of endolysosomal compartments that show areduction in their dynamics. Finally, because lysosomes undergo constant dynamic regulation by the small Rab7 GTPase, we investigated the effect of PA treatment on its activity. Interestingly, we found PA treatment altered the activity of Rab7. Altogether, these results unveil the cellular process by which PA exposure impairs the autophagic flux. As impaired autophagy in hypothalamic neurons promotes obesity, and balanced autophagy is required to inhibit malignant transformation, this could affect tumor initiation, progression, and/or response to therapy of obesity-related cancers.

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus.

Wnt signaling constitutes a fundamental cellular and molecular pathway, necessary from proper embryogenesis to function-maintenance of fully developed complex organisms. In this regard, Wnt pathway plays a crucial role in both the development of the central nervous system and in maintaining the structure and function of the neuronal circuits, and it has been suggested that its dysregulation is critical in the onset of several pathologies including cancer and neurodegenerative disorders, such as Alzheimer's disease (AD). Due to its relevance in the maintenance of the neuronal activity and its involvement in the outbreak of devastating diseases, we explored the age-related changes in the expression of Wnt key components in the cortex and hippocampus of 7 to 72-months-old Octodon degus (O. degus), a Chilean long-living endemic rodent that has been proposed and used as a natural model for AD. We found a down-regulation in the expression of different Wnt ligands (Wnt3a, Wnt7a, and Wnt5a), as well as in the Wnt co-receptor LRP6. We also observed an increase in the activity of GSK-3ß related to the down-regulation of Wnt activity, a fact that was confirmed by a decreased expression of Wnt target genes. Relevantly, an important increase was found in secreted endogenous Wnt inhibitors, including the secreted-frizzled-related protein 1 and 2 (SFRP-1 and SFRP-2) and Dickkopf-1 (Dkk-1), all them antagonists at the cell surface. Furthermore, treatment with Andrographolide, a labdane diterpene obtained from Andrographis paniculata, prevents Wnt signaling loss in aging degus. Taken together, these results suggest that during the aging process Wnt signaling activity decreases in the brain of O. degus.

Stimulation of Melanocortin Receptor-4 (MC4R) Prevents Mitochondrial Damage Induced by Binge Ethanol Protocol in Adolescent Rat Hippocampus.

Binge drinking is a common pattern of adolescent alcohol consumption characterized by a high alcohol intake within a short period of time; which may seriously affect brain function, triggering in some cases an addictive behavior. Current evidence indicates that alcohol addictive conduct is related to the impairment of the Melanocortin System (MCS). This system participates in the regulation of food intake and promotes anti-inflammatory response in the brain. However, the cellular mechanisms involved in the protective effects induced by MCS against binge-alcohol intoxication are still unknown. Here, we studied the effects of MCS activation on mitochondrial and oxidative damage induced by a binge-like protocol in the hippocampus of adolescent rats. We used a pharmacological activator of MC4R (RO27-3225) and evaluated its effects against oxidative injury, mitochondrial failure, and bioenergetics impairment induced by binge ethanol protocol in the hippocampus of adolescent's rats. Our results indicate that MC4R agonist reduces hippocampal oxidative damage promoting antioxidant (Nrf-2) and mitochondrial biogenesis (PGC1-alpha) pathways in animals subjected to the binge-like protocol. Additionally, MC4R activation prevented mitochondrial potential loss and increased mitochondrial mass that were significantly reduced by binge ethanol protocol. Finally, RO27-3225 treatment increased ATP production and mitochondrial respiratory complex expression in adolescent rats exposed to ethanol. Altogether, these findings show that activation of the MCS pathway through MC4R prevents these negative effects of binge ethanol protocol, suggesting a possible role of the MCS in the reduction of the neurotoxic effects induced by alcohol intoxication in adolescents.

Premature synaptic mitochondrial dysfunction in the hippocampus during aging contributes to memory loss.

Aging is a process characterized by cognitive impairment and mitochondrial dysfunction. In neurons, these organelles are classified as synaptic and non-synaptic mitochondria depending on their localization. Interestingly, synaptic mitochondria from the cerebral cortex accumulate more damage and are more sensitive to swelling than non-synaptic mitochondria. The hippocampus is fundamental for learning and memory, synaptic processes with high energy demand. However, it is unknown if functional differences are found in synaptic and non-synaptic hippocampal mitochondria; and whether this could contribute to memory loss during aging. In this study, we used 3, 6, 12 and 18 month-old (mo) mice to evaluate hippocampal memory and the function of both synaptic and non-synaptic mitochondria. Our results indicate that recognition memory is impaired from 12mo, whereas spatial memory is impaired at 18mo. This was accompanied by a differential function of synaptic and non-synaptic mitochondria. Interestingly, we observed premature dysfunction of synaptic mitochondria at 12mo, indicated by increased ROS generation, reduced ATP production and higher sensitivity to calcium overload, an effect that is not observed in non-synaptic mitochondria. In addition, at 18mo both mitochondrial populations showed bioenergetic defects, but synaptic mitochondria were prone to swelling than non-synaptic mitochondria. Finally, we treated 2, 11, and 17mo mice with MitoQ or Curcumin (Cc) for 5 weeks, to determine if the prevention of synaptic mitochondrial dysfunction could attenuate memory loss. Our results indicate that reducing synaptic mitochondrial dysfunction is sufficient to decrease age-associated cognitive impairment. In conclusion, our results indicate that age-related alterations in ATP produced by synaptic mitochondria are correlated with decreases in spatial and object recognition memory and propose that the maintenance of functional synaptic mitochondria is critical to prevent memory loss during aging.

Evidence of Synaptic and Neurochemical Remodeling in the Retina of Aging Degus.

Accumulation of amyloid-beta (Aß) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer's disease (AD) patients. In the eye, accumulation of Aß peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aß levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aß accumulation. We have employed the Octodon degus in which Aß peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aß peptide and phosphorylated tau accumulation in the retina.

Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aß Aggregation.

Alzheimer's Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aß40. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30-100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aß40, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aß42 over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia.

Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D.

Aging is an irreversible process and the primary risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial impairment is a process that generates oxidative damage and ATP deficit; both factors are important in the memory decline showed during normal aging and AD. Tau is a microtubule-associated protein, with a strong influence on both the morphology and physiology of neurons. In AD, tau protein undergoes post-translational modifications, which could play a relevant role in the onset and progression of this disease. Also, these abnormal forms of tau could be present during the physiological aging that could be related to memory impairment present during this stage. We previously showed that tau ablation improves mitochondrial function and cognitive abilities in young wild-type mice. However, the possible contribution of tau during aging that could predispose to the development of AD is unclear. Here, we show that tau deletion prevents cognitive impairment and improves mitochondrial function during normal aging as indicated by a reduction in oxidative damage and increased ATP production. Notably, we observed a decrease in cyclophilin-D (CypD) levels in aged tau-/- mice, resulting in increased calcium buffering and reduced mitochondrial permeability transition pore (mPTP) opening. The mPTP is a mitochondrial structure, whose opening is dependent on CypD expression, and new evidence suggests that this could play an essential role in the neurodegenerative process showed during AD. In contrast, hippocampal CypD overexpression in aged tau-/- mice impairs mitochondrial function evidenced by an ATP deficit, increased mPTP opening, and memory loss; all effects were observed in the AD pathology. Our results indicate that the absence of tau prevents age-associated cognitive impairment by maintaining mitochondrial function and reducing mPTP opening through a CypD-dependent mechanism. These findings are novel and represent an important advance in the study of how tau contributes to the cognitive and mitochondrial failure present during aging and AD in the brain.

Alcohol impairs hippocampal function: From NMDA receptor synaptic transmission to mitochondrial function.

Many studies have reported that alcohol produces harmful effects on several brain structures, including the hippocampus, in both rodents and humans. The hippocampus is one of the most studied areas of the brain due to its function in learning and memory, and a lot of evidence suggests that hippocampal failure is responsible for the cognitive loss present in individuals with recurrent alcohol consumption. Mitochondria are organelles that generate the energy needed for the brain to maintain neuronal communication, and their functional failure is considered a mediator of the synaptic dysfunction induced by alcohol. In this review, we discuss the mechanisms of how alcohol exposure affects neuronal communication through the impairment of glutamate receptor (NMDAR) activity, neuroinflammatory events and oxidative damage observed after alcohol exposure, all processes under the umbrella of mitochondrial function. Finally, we discuss the direct role of mitochondrial dysfunction mediating cognitive and memory decline produced by alcohol exposure and their consequences associated with neurodegeneration.

Publisher Correction: Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.

GALECTIN-8 Is a Neuroprotective Factor in the Brain that Can Be Neutralized by Human Autoantibodies.

Galectin-8 (Gal-8) is a glycan-binding protein that modulates a variety of cellular processes interacting with cell surface glycoproteins. Neutralizing anti-Gal-8 antibodies that block Gal-8 functions have been described in autoimmune and inflammatory disorders, likely playing pathogenic roles. In the brain, Gal-8 is highly expressed in the choroid plexus and accordingly has been detected in human cerebrospinal fluid. It protects against central nervous system autoimmune damage through its immune-suppressive potential. Whether Gal-8 plays a direct role upon neurons remains unknown. Here, we show that Gal-8 protects hippocampal neurons in primary culture against damaging conditions such as nutrient deprivation, glutamate-induced excitotoxicity, hydrogen peroxide (H2O2)-induced oxidative stress, and ß-amyloid oligomers (Aßo). This protective action is manifested even after 2 h of exposure to the harmful condition. Pull-down assays demonstrate binding of Gal-8 to selected ß1-integrins, including α3 and α5ß1. Furthermore, Gal-8 activates ß1-integrins, ERK1/2, and PI3K/AKT signaling pathways that mediate neuroprotection. Hippocampal neurons in primary culture produce and secrete Gal-8, and their survival decreases upon incubation with human function-blocking Gal-8 autoantibodies obtained from lupus patients. Despite the low levels of Gal-8 expression detected by real-time PCR in hippocampus, compared with other brain regions, the complete lack of Gal-8 in Gal-8 KO mice determines higher levels of apoptosis upon H2O2 stereotaxic injection in this region. Therefore, endogenous Gal-8 likely contributes to generate a neuroprotective environment in the brain, which might be eventually counteracted by human function-blocking autoantibodies.