Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.

Karenia selliformis is a globally recognized dinoflagellate associated with harmful algal blooms and massive fish kills along southern Chilean coasts. Its toxicity varies with environmental factors and genetic diversity. While K. selliformis is traditionally linked to neurotoxins like gymnodimines (GYMs), analysis of the strain CREAN-KS02 from Chile’s Aysén Region (43° S) revealed no presence of toxins associated with this genus, such as gymnodimines, brevetoxins, or brevenal. Given the high toxicity and impact on marine life, our study aimed to functionally characterize the neurotoxic metabolites in the exudate of K. selliformis cultures. Cytotoxicity was evaluated using a Neuro-2a cell-based assay (CBA), determining an IC₅₀ of 2.41 ± 0.02 μg mL⁻¹. The incubation of Neuro-2a cells with the bioactive lipophilic extract obtained from the exudate of K. selliformis and the ouabain/veratridine couple showed activation of voltage-gated ion channels. Electrophysiological recordings on cultured mouse hippocampal neurons showed that the extract increased cell excitability in a dose-dependent manner, modulating action potential firing and exhibiting an opposed effect to tetrodotoxin. These findings indicate the presence of excitatory neurotoxic compounds affecting mammalian cells. This study provides the first mechanistic evidence of K. selliformis toxicity and highlights potential risks associated with its proliferation in marine environments.

Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

Mitochondria act as a central integrative hub for oxidative phosphorylation, calcium homeostasis and metabolic signaling, reflecting their evolutionary origin from an α-proteobacterial endosymbiont. Although nearly 90% of their ancestral genes have been transferred to the nuclear genome, their role extends far beyond energy production. Emerging evidence positions mitochondria as active modulators of stress responses, which we term the “Mito-Mood Hypothesis.” This framework proposes that mitochondrial dynamics actively regulate gene expression and signaling, thereby shaping vulnerability to mood disorders such as depression, dysthymia, and seasonal affective disorder. Consistent with this view, patients with major depressive disorders show altered expression of nuclear-encoded mitochondrial genes, linking bioenergetics directly to psychiatric risk. We further discuss how oxidative phosphorylation (OXPHOS) modulates neurotransmitter cycles and how mitohormesis—adaptive responses to mild mitochondrial stress—can enhance resilience and cognition. Beyond psychiatry, mitochondrial vulnerability manifests in clinical settings: patients with mitochondrial diseases face elevated anesthetic risk, where agents such as propofol or volatile anesthetics may precipitate life-threatening metabolic crises. Collectively, these insights underscore mitochondria as central regulators of human health and highlight novel therapeutic opportunities bridging mood disorders and perioperative medicine.

Gelsemine, a naturally occurring indole alkaloid derived from plants of the Gelsemium species of the Gelsemiaceae family, has been extensively investigated for its neuroprotective and anti-inflammatory properties. Recent studies have demonstrated that gelsemine exerts neuroprotective effects against beta-amyloid (Aβ) oligomers, a key neurotoxic peptide implicated in the pathogenesis of Alzheimer’s disease (AD). However, despite these beneficial effects, the precise molecular targets underlying gelsemine’s neuroprotective actions in AD remain unidentified. Here, we employed a combination of bioinformatic, biochemical, and functional assays in neuronal models to investigate the mechanism of gelsemine’s action in AD cellular models. Our findings indicate that gelsemine inhibits the activity of transglutaminase 2 (TG2), an enzyme involved in protein cross-linking with emerging roles in Aβ aggregation and neurotoxicity. Molecular modeling and biochemical analyses reveal that gelsemine interacts with the TG2 catalytic site, leading to its inhibition. Furthermore, gelsemine modulates the TG2-mediated Aβ aggregation process, thereby attenuating Aβ-induced neurotoxicity and preserving neuronal function. These findings establish TG2 as a previously unrecognized molecular target of gelsemine and underscore the potential of Gelsemium-derived alkaloids as neuroprotective agents. The modulation of TG2 activity by natural alkaloids may provide a novel therapeutic approach for mitigating Aβ toxicity and preserving neuronal function in AD.