Mitochondrial anchoring and transport are essential to compensate for the altered energy demands at different ends of neuronal cells. Cells carefully control their mitochondrial movement to balance energy requirements and prevent death (Hollenbeck and Saxton, 2005). Because of their extremely extended architecture and specific functions, neurons are especially prone to interruptions in the dispersion and mobility of mitochondria. The control of mitochondrial mobility is crucial for both neuronal survival and degeneration (Lovas and Wang, 2013).

Two types of mitochondrial movements occur in neurons: anterograde and retrograde (Mandal and Drerup, 2019). Both these mitochondrial movements, throughout the neurons, are supported by cytoplasmic dynein motors for retrograde and kinesin-1 for anterograde movement (Hollenbeck and Saxton, 2005; Mandal et al., 2021; Pilling et al., 2006; Schnapp and Reese, 1989; Tanaka et al., 1998). Anterograde transport helps axon extension and regeneration for proper signal transmission by moving healthy mitochondria toward axon terminals and away from the cell body (Han et al., 2016; Morris and Hollenbeck, 1993; Ruthel and Hollenbeck, 2003; Spillane et al., 2013; Zhou et al., 2016). The injured mitochondria, on the other hand, migrate away from the axon terminals because retrograde mitochondrial transport is mostly in charge of removing and labeling damaged organelles and starting their breakdown within the cell body (Cai et al., 2012; Mandal et al., 2021; Frederick and Shaw, 2007; Miller and Sheetz, 2004). Trak1/2 (Guo et al., 2005; Stowers et al., 2002) and Rho GTPase 1 (Rhot1) are the two main adapter proteins implicated in anterograde migration. While Trak2 predominantly binds to dynein, Trak1 also attaches to kinesin-1. Nevertheless, insufficient proof exists to draw a firm connection between Trak2 activity and retrograde transit (van Spronsen et al., 2013). Actr10 is a different protein that helps mitochondria travel along the cytoskeleton in healthy neurons, ensuring these organelles are distributed and operate correctly. A critical link between dynein and mitochondria was established when deleting the Actr10 gene from zebrafish neurons impaired only the retrograde but not anterograde mitochondrial transport or the transport of other cargo (Drerup et al., 2017). Their movement mechanism must be studied to comprehend the function of mitochondria in neurons.

Mitochondrial movement is also responsible for removing aging and damaged mitochondria from the distal ends of neurons and maintaining neuron health (Palikaras et al., 2018). Mitochondrial mobility promotes mitophagy by guaranteeing that damaged mitochondria are carried retrogradely toward the cell body, where the autophagic machinery is more prevalent. Once within the cell body, damaged mitochondria are identified by mitophagy receptors and are removed selectively (Sheng, 2014).

The optimal calcium ion (Ca²⁺) level is key to neuronal health. Several neuronal functions, such as the release of neurotransmitters, synaptic plasticity, and signal transmission, are highly dependent on Ca²⁺ homeostasis (Jedrzejewska-Szmek et al., 2023). As important secondary messengers in various processes necessary for efficient communication within the nervous system, Ca²⁺ is pivotal for transmitting signals in neurons (Brini et al., 2014). An action potential triggers the opening of voltage-gated Ca²⁺ channels that reach the axon terminal of a neuron, letting Ca²⁺ enter the cell (Iosub et al., 2015; Werth and Thayer, 1994). Neurotransmitters are released into the synaptic cleft when synaptic vesicles fuse with the presynaptic membrane due to Ca²⁺ inflow. The signal can then continue to be transmitted once these neurotransmitters attach themselves to postsynaptic neuron receptors (Littleton et al., 1999). Long-term potentiation and depression, two synaptic plasticity mechanisms vital for learning and memory, are supported by this process and rely heavily on Ca²⁺ signaling. Depending on the activity, Ca²⁺ triggers different signaling pathways and kinases that alter the structure and responsiveness of synapses by either strengthening or weakening synaptic connections (Abraham et al., 2019). Ca²⁺ also activates various transcription factors (such as cAMP response element-binding protein, nuclear factor of activated T-cells, and myocyte enhancer factor-2), thus regulating the expression of crucial genes that influence differentiation, growth, and neuronal response to external stimuli (Bagur and Hajnoczky, 2017). Moreover, the optimal level of Ca²⁺ ensures appropriate neural circuit creation during neuronal development as the Ca²⁺ gradients direct growth cones and control neurite outgrowth (Park and Poo, 2013).

Synaptic mitochondria mediate the process of buffering and transfer of intracellular Ca²⁺ levels, facilitating neurotransmission (Billups and Forsythe, 2002; Kann and Kovacs, 2007; Kim et al., 2011; Levy et al., 2003; Rizzuto et al., 2012). By rapidly absorbing and releasing Ca²⁺ via the Na⁺/Ca²⁺ exchanger and mitochondrial calcium uniporter (MCU), respectively (as explained later in the section), these organelles can maintain Ca²⁺ homeostasis (Shoshan-Barmatz and De, 2017). Mitochondria mitigate the cytotoxicity linked to increased Ca²⁺ levels by sequestering surplus Ca²⁺ during neural activation and regulating the spatiotemporal dynamics of Ca²⁺ signaling, ensuring proper neuronal survival and function (Giorgi et al., 2018a).

Voltage-gated Ca²⁺ channels at the presynaptic terminal activate during neuronal depolarisation, facilitating Ca²⁺ influx and initiating neurotransmitter release (Sudhof, 2012). The mitochondrial membrane potential, produced by the electron transport chain, enables Ca²⁺ influx into the mitochondrial matrix (Kann and Kovacs, 2007; Rizzuto et al., 2012). Baseline cytosolic and mitochondrial Ca²⁺ concentrations are approximately 100 nM, but increase during Na⁺ channel-mediated depolarisation. Dendritic mitochondria mitigate this rise and assist in reinstating the resting potential (Billups and Forsythe, 2002; Burke et al., 2001). Calcium ions (Ca²⁺) ingress into mitochondria through voltage-dependent anion channels and the mitochondrial calcium uniporter (MCU), modulating synaptic efficacy and neurotransmitter secretion (Giorgi et al., 2018b; Kim et al., 2011). Mitochondrial depolarisation influences mtDNA and synaptic vesicle dynamics (Kim et al., 2011). Fusion improves Ca²⁺ uptake efficiency by altering mitochondrial structure and membrane potential (Kowaltowski et al., 2019; Trevisan et al., 2018). Dendritic mitochondria in the postsynaptic neuron undergo fission to modulate Ca²⁺ uptake and sustain signalling efficacy (Divakaruni et al., 2018; Han et al., 2008; Rangaraju et al., 2019a). Mitochondrial Ca²⁺ furthermore activates tricarboxylic acid cycle enzymes, enhancing ATP synthesis to fulfil neural energy requirements (Denton et al., 1978; Jouaville et al., 1999).

Neurons are particularly demanding because of their intricate signal transmission and information processing functions. The balance in mitochondrial metabolism is integral for sustaining neurotransmission, preserving ion gradients throughout the cell membrane, facilitating synaptic formation and plasticity, and releasing synaptic vesicles (Cai and Tammineni, 2017; Hall et al., 2012). Mitochondrial ATP production plays a pivotal role in fulfilling this high energy demand, ensuring appropriate neuronal functioning (Rossi and Pekkurnaz, 2019). Numerous studies have elucidated the critical relationship between mitochondrial ATP production and neuronal activities. For instance, research has highlighted the significance of OXPHOS in generating ATP within neuronal mitochondria under high energy demands rather than depending on glycolysis.

Deteriorated mitochondrial ATP production can result in energy deficits, compromising neuronal viability and functionality (Clemente-Suarez et al., 2023). Regardless of their primary causation, disturbances in mitochondrial functions contribute to neuronal demise and are implicated in various neurological conditions, such as amyotrophic lateral sclerosis (ALS), PD, AD, Huntington’s disease (HD), spinocerebellar ataxia and peripheral neuropathies such as Charcot–Marie–Tooth disease (Pass et al., 2021). Observable signs of mitochondrial dysfunction include decreased respiratory chain complex activity, which always affects ATP synthesis (Zhao et al., 2022). Furthermore, recent research has focused on the association between mitochondrial function and aging, reporting that mitochondria become less efficient with age, leading to decreased neuronal function. This mitochondrial performance reduction has been further linked to age-related cognitive decline and NDDs (Chistiakov et al., 2014).

Mitochondria undergo constant fission and fusion, along with mitophagy, to maintain their quality and function. These dynamic processes are essential for neuronal health (Cheng et al., 2010; Detmer and Chan, 2007). The intricate interaction of molecular machinery closely controls these processes. Mitofusins (MFN1 and MFN2) mediate fusion of outer mitochondrial membrane (OMM) by forming homo- and heterodimers (Cipolat et al., 2004). OPA1 facilitates inner mitochondrial membrane (IMM) fusion (MacVicar and Langer, 2016). Fission is driven by DRP1, a GTPase that oligomerizes at the OMM to constrict and divide mitochondria, with support from mitochondrial fission protein 1 FIS1 (Fonseca et al., 2019; Otera et al., 2010).

Fission enables mitochondrial transport to energy-demanding regions like axons and synapses, ensuring ATP availability for neural signaling. It also isolates damaged segments for removal via mitophagy (Trevisan et al., 2018). On the other hand, the process of fusion supports mitochondrial integrity by forming networks that enhance bioenergetics, calcium buffering, and synaptic function (Berman et al., 2008; Westermann, 2010).

Apart from fission and fusion, mitophagy is also an essential cellular quality control process. It involves the breakdown of defective and unnecessary mitochondria via macroautophagy. This safeguarding mechanism ensures the optimal functioning of the mitochondrial network, enabling it to adapt to the constantly changing physiological requirements (Kanki et al., 2010; Sarraf et al., 2013; Palikaras et al., 2018; Yamashita et al., 2016). Proteins such as OPA-1, DRP1, and MFN2 not only initiate mitophagy but also influence the production of autophagosomes and regulate mitochondrial activity. In addition, the start of mitophagy requires PTEN-induced putative kinase 1 (PINK1) and E3-ubiquitin ligase protein (parkin). To ubiquitinate target proteins, these proteins accumulate on the OMM (Lazarou et al., 2013; Wibawa et al., 2015). In a well-studied mitophagy model, a disturbed membrane potential keeps PINK1 from entering mitochondria and stabilizes it on the outer membrane (Narendra et al., 2010). Subsequently, PINK1 phosphorylates ubiquitin moieties on various protein substrates, including parkin, initiating its recruitment and activation in the proximity of the OMM (Ng et al., 2014). Activated parkin ubiquitinates OMM protein, enabling the recognition of autophagic adapters on their journey toward mitochondrial degradation in the lysosomes.

The well-established correlation between mutation in parkin and PINK1 and the prevalence of autosomal recessive cases of PD highlights the importance of this complex regulatory mechanism (de Oliveira et al., 2021). Mitophagy and autophagy are crucial for promoting longevity, and both these processes tend to decline with advancing age (Palikaras et al., 2017). Inhibiting mitophagy has been linked to a reduced lifespan, whereas fostering autophagy has been associated with an extended lifespan (Kissova et al., 2004; Melendez et al., 2003). While the mechanisms underlying these relationships are not completely understood, efficient mitophagy has been hypothesized to mitigate mitochondria-associated oxidative stress and lessen the number of damaged mitochondria with mtDNA mutations. The neurological system is particularly prone to mitochondrial malfunction because of its increased energy requirements. Impaired mitophagy is implicated in neuropathologies observed in certain familial variations of HD, AD, and PD, making it a potential therapeutic target (Trigo et al., 2022).

Neuroinflammation is significantly associated with the pathogenic aspect of Alzheimer’s and is characterized by a complex interplay of cellular and molecular mechanisms that contribute to progressive neurodegeneration. Glial cell stimulation, immune cell translocation from the peripheral system, amyloid beta (Aβ) plaque accumulation, and neurofibrillary tangles (NFTs) are components of the neuroinflammatory response in AD (Heneka et al., 2015). Cerebral inflammation in Alzheimer’s disease is distinguished by the stimulation of microglial cells and astrocyte cells at the cellular scale. When activated, these supportive brain cells secrete various proinflammatory substances, including cytokines (such as interleukin 1β and 6 and TNF), chemokines, ROS, and other inflammatory mediators that trigger an immune response. This inflammatory milieu exacerbates neurotoxicity, leading to excessive neural cell death and fueling the neuroinflammatory cascade. The invasion of immune cells in the outer regions, including lymphocytes and monocytes, into the brain parenchyma also occurs in AD, amplifying the inflammatory response. These invading cells secrete extra-inflammatory substances and continue the cycle of neuroinflammation and neurodegeneration (Kaur et al., 2019). The major contributor to neuroinflammation in AD is the accumulation of Aβ plaques and NFTs, which induces neurotoxicity, leading to excessive neural cell death via apoptosis, autophagy, and necroptosis (Onyango et al., 2021). This process establishes a positive feedback loop in which elevated neuroinflammation results in neurodegeneration. At the molecular level, neuroinflammation in AD disrupts transcriptional mechanisms, affecting the expression of genes encoding proinflammatory cytokines such as IL-1β, 6, and TNF. NF-κB controls microglial activation to regulate the process of neuroinflammation. In addition, activating the inflammasome NLRP3 in microglia promotes IL-1β production, leading to persistent inflammatory reactions in AD (Li et al., 2022). The buildup of Aβ in mitochondria disrupts mitochondrial function and increases the production of ROS that activate inflammatory signaling pathways, exacerbating neuroinflammation. Excessive accumulation of Aβ and tau impairs autophagic function, hindering protein clearance and augmenting neuroinflammation and neuronal degeneration (de la Cueva et al., 2022).

In Parkinson’s, an intricate network of cellular and molecular mechanisms collaborates to degenerate nerve cells that produce dopamine within the substantia nigra pars compacta part of the midbrain. During this inflammatory reaction, reactive glial cells release numerous inflammation-promoting cytokines, chemokines, ROS, and other inflammatory mediators, creating a toxic environment that exacerbates nerve cell deterioration. The dysregulation of cytokine levels is a key aspect of neuroinflammation in PD (Di Lazzaro et al., 2023). Neurodegeneration is accelerated in the brain of patients with PD owing to increased amounts of inflammation-promoting signaling molecules, such as IFN-γ, IL-1β, 6, and TNF (Isik et al., 2023). Moreover, anti-inflammatory signaling molecules, such as IL-10 and transforming growth factor beta (TGF-β), are improperly regulated, further disturbing the delicate equilibrium of inflammatory mediators (Belarbi et al., 2020). In PD, glial cells are activated, and immune-specific cells such as T lymphocytes, monocytic cells, and macrophages from the external environment infiltrate the brain parenchyma. This infiltration increases the potency of the inflammatory response. These infiltrating cells can release additional inflammatory mediators and exacerbate the neuroinflammatory cascade (Munoz-Delgado et al., 2023).

At the molecular level, genetic factors are crucial in the development of PD and the initiation of neuroinflammatory processes. Genetic alterations in several proteins have been indicated in the accumulation of misfolded PD-associated proteins. These changes encompass genetic variations in the genes encoding α-synuclein (SNCA), glucocerebrosidase (GBA), vacuolar protein sorting 35 (VPS35), and leucine-rich repeat kinase 2 (LRRK2). These modifications activate inflammatory signaling pathways, triggering glial cell activation (Yao et al., 2021). Neuroinflammation in PD also involves the dysregulation of transcriptional processes, affecting the expression of inflammatory genes. NF-κB controls the production of different cytokines that promote inflammation and has a vital function in activating microglia and, thus, the inflammation process (Tiwari and Pal, 2017).

Microglia, the primary agents in brain inflammation (Woodburn et al., 2021), can assume either an M1 or an M2 macrophage state. Microglial transformation to the M1 phenotype from the M2 state contributes to neuroinflammation and neurodegeneration in PD. In addition, NLRP3 inflammasome activation in microglia releases pro-inflammatory cytokines such as IL-1β, intensifying neuroinflammation in PD. Mitochondrial dysfunction and increased ROS synthesis, which are hallmarks of PD pathology, can also activate inflammation-associated molecular pathways. This interaction among inflammation, oxidative damage, and mitochondrial impairment establishes a self-sustaining cycle that propels the ongoing degeneration of dopamine-producing neurons in PD (Pizarro-Galleguillos et al., 2023).

The primary factor responsible for immune-mediated inflammation and dysregulated molecular pathways observed in HD is the accommodation of mHtt (mutant huntingtin protein) containing an elongated polyglutamine repeat. mHtt initiates a self-perpetuating cycle of neuroinflammation and neurodegeneration via multiple mechanisms. Initially, the misfolding and aggregation of mHtt activate the NF-κB signaling pathway without any intermediaries or NLRP3 inflammasome (Saba et al., 2022). These aggregates also impair protein homeostasis by interfering with the ubiquitin–proteasome system and autophagic processes, accumulating improperly folded proteins. This buildup activates UPR and induces stress in the ER, exacerbating inflammatory reactions. Furthermore, mHtt associates with mitochondria, leading to mitochondrial impairment and elevated ROS generation, triggering inflammatory signaling cascades and promoting the release of immune-activating cytokines. The presence of mHtt aggregates and the associated stress further activate microglia along with astrocytes, producing inflammatory mediators (Saba et al., 2022). Transcriptional dysregulation is another key aspect of HD pathogenesis. mHtt interferes with transcriptional regulators such as CREB-binding protein and histone deacetylases (HDACs), altering gene expression, including that of inflammatory genes. Furthermore, mHtt can induce epigenetic changes, such as histone modifications and DNA methylation, affecting the expression of proinflammatory and anti-inflammatory genes. Moreover, mHtt disrupts the function of transcriptional regulators implicated in immune responses, including NF-κB, AP-1, and STAT3, modifying the expression of their downstream genes (Pogoda et al., 2021). Impaired clearance mechanisms exacerbate this cycle as inflammation and autophagy dysfunction impair the clearance of mHtt aggregates, enhancing their accumulation (Pircs et al., 2022). Comprehending the intricate neuroinflammation pathway and the underlying molecular biology in HD is crucial to developing precise therapeutic strategies that can break the vicious cycle and potentially slow the progression of this devastating neurodegenerative disease.

MS is a condition in which the body’s immune system erroneously targets and damages the protective myelin sheath in the CNS. Autoreactive myeloid cells and lymphocytes invade the CNS, triggering an inflammatory response that drives the pathogenesis of MS (Papiri et al., 2023). On the cellular scale, brain inflammation in MS is marked by stimulating microglial cells, glial cells, and oligodendrocytes within the CNS (Amoriello et al., 2024). These reactive supportive cells secrete diverse inflammatory signaling molecules, fueling the inflammatory cascade. Dysregulation of cytokine levels, particularly those of TNF, IL-17, and granulocyte–macrophage colony-stimulating factor (GM-CSF), contributes to the pathogenesis of MS (Amoriello et al., 2024). The inflammatory environment leads to synaptopathy, a process characterized by synaptic loss, reduced synaptic protein levels, and altered neurotransmission in MS (Mandolesi et al., 2014; Nisticò et al., 2017; Depino et al., 2003). Cytokines such as TNF modulate glutamatergic neurotransmission by altering the expression and functional properties of AMPA receptors, contributing to synaptic dysfunction. This dysregulation of neurotransmission precedes the symptomatic phase in animal models of MS (Bruno et al., 2020). Activated microglia near axon terminals cause local calcium overload and spine removal, exacerbating neuronal damage. Cytokines such as GM-CSF stimulate the activation and growth of microglial cells, resulting in altered neural network patterns and excitability. Moreover, various cytokines, such as IL-17 and GM-CSF, can interact and worsen neuronal alterations during disease exacerbations, highlighting the complexity of the neuroinflammatory processes in MS (Amoriello et al., 2024). At the molecular level, neuroinflammation in MS involves epigenetic changes and dysregulation of transcriptional processes, affecting inflammatory gene expression (Huynh and Casaccia, 2013). These epigenetic modifications and transcriptional dysregulation perpetuate the inflammatory cascade and neurodegeneration. The neuroinflammatory processes and molecular mechanisms in MS culminate in synaptopathy, neurodegeneration, and the development of neurological deficits in patients (Ellwardt and Zipp, 2014).

Neuroinflammation in the CNS is a prominent feature of ALS and is observed in both experimental setups and individuals diagnosed with this disorder. The invading immune cells, as well as resident microglial cells and astrocytes, activate the immune reaction and interact with multiple cellular components. Microglia play a vital role in the process of neuroinflammation in ALS. These cells can assume either a harmful M1 or a beneficial M2 phenotype. After the initiation of ALS in mouse models, the cellular transition of microglia from the M2 to the M1 state leads to neural inflammation and disease progression (Geloso et al., 2017). In addition, activating the NLRP3 inflammasome in microglia is a prominent factor that promotes neuroinflammation in ALS. Astrocytes, a specific type of brain cells that provide support, are also involved in the inflammatory process in ALS. These cells secrete a range of signaling proteins, including proinflammatory and anti-inflammatory mediators. Proinflammatory molecules such as IL-1, IL-6, and TNF and anti-inflammatory mediators such as prostaglandin E2 and TGF-β are mainly released (Peggion et al., 2024). Astrocytes generated from fibroblasts of ALS patients, via trans-differentiation method, exhibited toxicity toward motor neurons cocultured with them, possibly due to compromised bioenergetic support or impaired signaling of pro-nerve growth factors (Gomes et al., 2022). Infiltration of lymphocytes and macrophages into the CNS is also noted in ALS, amplifying the inflammatory response. The NF-κB protein is a pivotal regulator of inflammation in ALS, controlling microglial activation and the occurrence of neuroinflammation (Geloso et al., 2017). At the molecular level, neuroinflammation in ALS involves the dysregulation of transcriptional processes, altering the gene expression of several inflammatory mediators. ER stress and RNA metabolism disruption have also been implicated in the development of ALS, potentially contributing to neuroinflammation. This complex interplay of cellular players and molecular mechanisms drives the neuroinflammatory processes in ALS, ultimately resulting in motor neuron dysfunction and death.

Neuroinflammation is pivotal in the pathophysiology of schizophrenia, epilepsy, and autism spectrum disorders (ASD) by impairing neuronal connection, neurotransmission, and cerebral development. In schizophrenia, increased cytokines such as IL-6 and TNF-α disrupt dopamine and glutamate pathways, exacerbating symptoms, while hyperactive microglia induce excessive synaptic pruning and impair the blood–brain barrier, leading to additional neurotoxicity (Mosquera et al., 2024; Ermakov et al., 2023; Ayilara and Owoyele, 2023). Early-life inflammatory exposures, including maternal infections, elevate the risk of schizophrenia by disrupting brain development, as evidenced by heightened microglial activity and elevated cytokine levels (Buckley, 2019). These results have initiated trials of anti-inflammatory treatments, encompassing NSAIDs, monoclonal antibodies, and lifestyle modifications (Sommer et al., 2011; Essali et al., 2019; Gurusamy et al., 2024). In epilepsy, proinflammatory cytokines such as IL-1β and TNF-α increase neuronal excitability and diminish GABAergic inhibition, facilitating seizures via blood-brain barrier disruption, neuronal degeneration, and dysfunctional synaptic networks (Pracucci et al., 2021; Sanz et al., 2024; Li et al., 2023). Seizures exacerbate inflammation, establishing a detrimental cycle, with medications aimed at IL-1β and TNF-α pathways currently under examination (Ravizza et al., 2024; Panina et al., 2023; Mukhtar, 2024). In ASD, neuroinflammation impairs neuronal differentiation and synaptic integrity through cytokines generated by activated glial cells (Xiong et al., 2023; Usui et al., 2023). Maternal immune activation during gestation increases the likelihood of autism spectrum disorder by modifying foetal neural circuit development, whereas postnatal inflammation impacts brain areas such as the prefrontal cortex and amygdala, leading to fundamental behavioural abnormalities (Yin et al., 2023; Tan et al., 2024; Hughes et al., 2022). In genetic mouse models of ASD, cerebellar and systemic inflammation, often accompanied by oxidative stress, contribute to behavioural and motor deficits. N-acetylcysteine (NAC) treatment improved these impairments in Cntnap2 and Shank3b mutant mice, highlighting the interplay between neuroimmune dysfunction, oxidative stress, and aging in ASD pathophysiology (Pangrazzi et al., 2025; Pangrazzi et al., 2024; Cerilli et al., 2024).

Similar to mitochondrial dysfunction leading to neuroinflammation, neuroinflammation also affects mitochondrial function and increases the severity of the phenotype in various neurological conditions, as illustrated in Figure 4.