A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson’s disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response.

Microglia play a significant role in the development and progression of Alzheimer's disease (AD). These brain-resident immune cells efficiently clear neurotoxic amyloid beta (Aβ) peptides; however, chronic activation may overwhelm their protective abilities, resulting in persistent neuroinflammation. The causes of aberrant microglial activation in AD remain elusive. Emerging evidence indicates that copper (Cu) accumulation, which can arise from prolonged exposure to various environmental sources, modifies the innate immune response in AD. Here, we sought to explore the mechanisms by which Cu overload regulates the microglial phenotype when exposed to Aβ. Our findings showed that exposure to sublethal doses of Cu led to the accumulation of this transition metal in the mitochondria. Elevated mitochondrial Cu (mtCu) levels were accompanied by reduced mitochondrial glutathione (mtGSH) and high oxidative stress, leading to Aβ-induced inflammasome activation through the release of oxidized mitochondrial DNA (ox-mtDNA). Moreover, increased intracellular Cu levels enhanced cholesterol biosynthesis and facilitated its transport to mitochondria. The combination of elevated cholesterol and mitochondrial oxidative stress hindered the ability of microglia to phagocytose Aβ effectively. As expected, conditioned medium from Cu-activated microglia reduced neuronal viability. The neurotoxicity caused by Cu-overloaded microglia was prevented by inhibiting inflammasome activation and restoring mtGSH levels. In conclusion, our study outlines a mechanistic pathway by which chronic exposure to environmental Cu may lead to neuroinflammation and Aβ accumulation in AD, underscoring the crucial role of mitochondrial oxidative stress.

Copper (Cu) is an essential trace metal; however, its dysregulation promotes oxidative stress and contributes to neurodegeneration. Astrocytes are central to neuronal homeostasis, in part through extracellular vesicle (EV)-mediated communication, yet they are particularly vulnerable to metal-induced oxidative damage. Under pathological conditions, astrocyte-derived EVs can acquire neurotoxic properties, thereby amplifying neuronal injury. However, the mechanisms governing neuron–glia crosstalk under Cu overload remain incompletely defined. Here, we show that sublethal Cu exposure induces mitochondrial oxidative stress in astrocytes, leading to redox-dependent reprogramming of cholesterol metabolism and alterations in EV release. EVs derived from Cu-overloaded astrocytes propagate oxidative damage to neurons, establishing a ROS-driven pathway of glia-to-neuron communication. Notably, activation of insulin-like growth factor 1 (IGF-1) signaling—via recombinant protein or adenoviral delivery—attenuates Cu-induced oxidative stress, partially restores cholesterol metabolic homeostasis, and reprograms astrocyte-derived EVs toward a non-cytotoxic phenotype. Collectively, these findings identify astrocyte-derived EVs as key mediators of Cu-induced neuronal injury and highlight IGF-1 signaling as a potential therapeutic strategy to preserve astrocyte oxidative resilience and neuroprotective function.