As, a widely distributed toxic metalloid, is a risk for about 200 million people in more than 24 countries around the world [156,157]. It can be absorbed through skin, digestive tract, and inhalation. After absorption, As can be distributed to various organs, including kidney, lung, liver, and spleen in the animal and human bodies [158,159]. More seriously, As can enter the central nervous system (CNS) through the BBB and accumulate in different brain regions [160,161,162]. In vivo studies showed that excessive exposure to As induced neuronal apoptosis, which interrupted the neurodevelopment and cognitive functions of rats [163,164,165]. Epidemiological studies in rural-dwelling adults and elders also show that As (3–15 µg/L) levels in water negatively correlated with the scores of cognitive performance and memory, indicating that As is a neurotoxic metalloid [166], which also acts as a risk factor for AD [33,167,168,169]. However, the mechanisms of As-induced neurotoxicity remain unclear.

To date, As-induced neurotoxicity has been related to Aβ overproduction [32,170], inflammatory responses [171,172], thiamine deficiency [173], oxidative stress, disruption of neurotransmitters [163,171], cytoskeletal gene expression, mitochondrial dysfunction, and disruption of acetyl cholinesterase activity [166,167,174]. Among them, mitochondrial dysfunction has been demonstrated to play a key role in As-induced neurotoxicity. Several in vitro studies have shown that As may induce adverse effects on mitochondrial functions. For example, Haga et al. [175] suggested that aggregated mitochondria were found in A172 cells after 50 μM arsenic trioxide (As₂O₃) treatment for 8 h. Subsequently, other investigators also suggested that sodium arsenite (NaAsO₂) or As₂O₃ treatment induced mitochondrial dysfunction via increasing intracellular Ca²⁺ levels, mitochondrial membrane potential (MMP), or calpain 1 levels in N₂A cells [176], SHSY-5Y cells [177], and primary astrocytes [178], as well as rats’ primary neuronal cells [179]. Moreover, in vivo studies have also verified the critical roles of oxidative stress and mitochondrial dysfunctions in As-induced neurotoxicity [180,181].

It is well known that the mitochondrion is the main source of ROS formation, as well as a major target of ROS [182]. Oxidative stress is closely related to mitochondrial dysfunctions induced by As. Yadav et al. [183] showed that the activities of oxidative stress marker enzymes MnSOD and CAT were decreased by As in the mitochondrial fraction of different brain regions (including striatum, hippocampus, and frontal cortex) of rats via increasing ROS, and lipid peroxidation after exposure to NaAsO₂ for 28 days [181,183]. Similar results were found in sub-chronic As exposure studies done by other investigators which indicated that MnSOD, CAT, Gpx, GR, and GST activity were decreased in the mitochondrial fraction of rat brain [184,185]. Moreover, various studies suggested that As directly impaired the mitochondrial respiratory system via oxidative stress. Dwivedi et al. [180] indicated that As caused oxidative stress which in turn inhibited the activities of complexes I, II, and IV in the mitochondria of rat brain. These results have been corroborated by other labs [181,185]. Furthermore, excessive As exposure disrupted oxidative phosphorylation, and thus interrupted the ATP synthesis and mitochondrial respiration in the mitochondria of the brain [180,186]. Consistent with these results, sub-chronic exposure to low levels of As has been shown to decrease gene expression of the mitochondrial complexes II, IV, and V in mice brains [187,188]. All of the above-mentioned studies suggested that the mechanisms of oxidative stress involved in As-induced mitochondrial dysfunctions play a pivotal role in As-induced neurotoxicity.

In summary, these studies suggest that the mitochondrial dysfunction in the CNS is the most important mechanism of As-induced neurotoxicity. It includes impairments of Ca²⁺ homeostasis [177,189], abnormal mitochondrial dynamics [190,191], and changes in membrane potential and permeability [174,192], which induces neuronal injuries via the mediating mitochondria-dependent pathway.

Al is a ubiquitously distributed metal on the earth, and it can be easily absorbed via skin contact, inhalation, and ingestion. Al sulfate has been ubiquitously used for water purifying, food processing, and the medicine and pharmaceutical industry, which ensure its presence in human bodies [193]. An increasing number of studies have shown that Al could accumulate in various mammalian organs, including bone, kidney, lung, liver, spleen, and brain [194,195,196]. Growing evidence has also suggested that Al accumulations in various brain regions may cause neurotoxic symptoms and learning impairment [196,197]. Studies in rodents indicated that chronic Al exposure led to Al accumulation in the hippocampus and caused neurobehavioral impairment [198,199,200]. Other studies also reported that Al caused neurofibrillary degeneration [197]. Altmann et al. showed that the impairment in cerebral function may be related to the concentrations of Al in the contaminated water [201]. Additionally, epidemiological studies suggested that Al has been considered as a potential risk factor in the development of neurodegenerative diseases, such as AD [196,202], PD [203,204], and ALS, etc. [205,206,207].

Several studies have proposed that mitochondrial dysfunction may play a critical role in the toxic effects of Al, including neurotoxicity [197,208]. Rao et al. [209] have shown that the ROS formation and mitochondrial respiratory activity, as well as glutathione depletion, were increased in the glial cells after being treated with Al for 24 h. Other groups have also depicted that Al exposure increased ROS formation and impaired the cytochrome c oxidase, which impaired mitochondrial functions in various neuronal cell types, including PC12 [210,211,212], SH-SY5Y neuroblastoma cells [213,214], and rat and cerebellar granule neuronal cells [42,215]. Mitochondrial dysfunction was also observed in in vivo studies [216,217]. Acute exposure to 50 μM Al maltonate via intracisternal injection caused the release of cytochrome c (cyt-c), accompanied by decreased Bcl-2, upregulated Bax, p53, and caspase-3, and DNA fragmentation in the mitochondria of rabbit brain [218]. Subsequently, Kumar et al. also reported that sub-chronic Al exposure for 12 weeks resulted in elevated ROS generation, and decreased ATP synthesis and cytochrome levels in a rat’s brain, which implied disruption of mitochondrial function [219]. In addition, their other study also suggested that Al exposure decreased MnSOD and aconitase activities in different regions of the rat brain [220]. Additionally, transmission electron microscope results showed that Al exposure caused mitochondrial swelling and vacuolization structures, and thus increased the diameter of mitochondria in the hippocampus nerve cells of mice and rats [208,219]. Finally, Al exposure upregulated the autophagy-related proteins LC3-II and Beclin-1, while downregulating p62 expression, suggesting that Al-induced learning and memory impairments may be related to mitophagy [208].

Recently, oxidative stress and mitochondrial disorders have been suggested as major targets for Al-induced neurotoxicity. For example, quercetin has shown protective effects on Al-induced mitochondrial swelling and chromatin condensation in rat hippocampus [221]. Naringin also has protective effects on memory impairment of sub-chronic Al-exposed rats via preventing the activations of mitochondrial oxidative damage in the brain [222]. Subsequently, Centella asiatica, which has antioxidant properties, was shown to ameliorate memory impairment and the activation of oxidative stress and decrease mitochondrial enzyme activity in the hippocampus and cerebral cortex induced by Al [223]. In addition, some other natural compounds also have been shown to have neuroprotective effects on Al-induced neurotoxicity, such as crocin, curcumin, and polyphenols [197,224,225]. These studies indicate that inhibition of oxidative stress and mitochondrial dysfunction may be a therapeutic strategy to prevent the neuronal injuries induced by Al.

Cu is an essential trace metal for human health. Cu takes part in many cellular enzymatic activities, including energy production, redox balance, and neurotransmitter biosynthesis [226]. An adequate amount of copper is critical for the maintenance of redox balance in the mitochondria [227]. The mitochondria are both a regulatory hub for Cu homeostasis and a target of Cu toxicity [228]. For example, Cu is required for metallation of the catalytic core of cytochrome c oxidase, a mitochondrial metalloenzyme in the respiratory complex chain [229]. However, overload of mitochondrial Cu is detrimental to the function of respiratory complexes, leading to elevation of ROS and mitochondria dysfunction. Wilson’s disease is a genetic disorder caused by excessive mitochondrial copper in the liver [227].

Brain mitochondria are particularly sensitive to the detrimental effects of Cu [230]. Compared to the mitochondria in the liver, kidney, and heart, brain mitochondria are susceptible to elevated levels of Cu, which attacks free thiols in large molecules that are indispensable for maintaining neuronal cell function [230]. The membrane potential, efficiency in ATP production, and structural integrity of brain mitochondria were prone to damage caused by excessive Cu [230]. Chronic Cu exposure led to spatial memory impairment that was associated with mitochondrial damage in the hippocampus [231]. Specifically, beta-amyloid-induced memory deficit in rats is exacerbated by Cu exposure. Meanwhile, analysis of isolated mitochondria from rat hippocampus following Cu exposure demonstrated a significant decline in mitochondria health, including increased lipid peroxidation and glutathione oxidation [231]. Mishandling of Cu in the mitochondria has been linked to age-related neurodegenerative disorders [232,233,234]. In a mice model of AD, a proteomics study showed that low levels of Cu exposure (0.13 ppm, 2 months) induced deficits in mitochondrial dynamics, leading to increased H₂O₂ production and reduced cytochrome oxidase activity [232]. Common biochemical characteristics of PD include accumulation of iron and diminished Cu content in degenerated brain regions. The disruption of Cu metabolism was believed to be involved in the pathological process in loss of catecholamine neurons [233]. Additionally, in a 6-hydroxydopamine (6-OHDA)-induced-PD model, Cu exposure increased oxidation of 6-OHDA, resulting in an increase in the rate of p-quinone formation and H₂O₂ accumulation. In the same model, the 6-OHDA-induced lipid peroxidation and protein oxidation were potentiated by Cu exposure [234].

Mitochondrial dysfunction following chronic Cu exposure involves oxidative stress, collapse in mitochondrial membrane potential, depletion of GSH, comprised function of respiratory complexes, reduction in APT production, and structural damage to the mitochondria [230,231]. Experimental evidence showed that free protein thiols in the mitochondria are potential toxic targets of Cu [230]. GSH supplementation attenuated Cu-induced lipid peroxidation but failed to protect oxidized thiols [234]. In addition, the induction of the mitochondrial permeability transition (MPT) was associated with Cu-induced astrocytic injury [235]. Furthermore, mitochondrial health in the hippocampus is a potential in vivo target of Cu. A recent study showed that mitochondrial biogenesis and respiratory function were impaired in the hippocampus of mice chronically exposed to CuCl₂ [232].

Cd is a heavy metal that has no nutritional roles for humans. Cd-induced cellular damage is largely mediated by disruption of mitochondrial activity [236]. Elevation of ROS in the mitochondria and induction of mitochondria-derived apoptosis signaling are involved in Cd-induced neurotoxicity [237,238]. Mitochondrial protection afforded by antioxidants can attenuate Cd-induced neuronal damage [239].

An elevation in protein and lipid peroxidation, decrease in antioxidant capacity, and structural damage to the mitochondria were shown in the brains of rats chronically exposed to Cd [240]. The structural stability of mitochondria-associated ER membranes (MAMs) is critical for the proper function of the mitochondria. Recent studies show that MAMs are not only the physical bridge to facilitate communication between the ER and mitochondria, but they are also indispensable for cellular homeostasis processes such as autophagy, lipid metabolism, and Ca²⁺ transport [241]. Cd exposure induced increased production of ROS in the mitochondria, leading to impairment of MAMs [242]. The shapes of mitochondria are subjected to transformations in response to cellular stress, which is driven by two closely related processes: mitochondrial fusion and fission. Mitochondrial fusion and fission are required for proper intracellular distribution and quality control of the organelle [243]. Mitofusin 2 (Mfn2) is a mitochondrial outer membrane-localized GTPase that is essential for mitochondrial fusion. Cd-induced neuronal necroptosis was associated with ROS-induced S-glutathionylation of Mfn2 [242]. Increased ROS levels are detrimental to the activity of key enzymes involved in lipid metabolism. Cd exposure altered the lipid profile in a rat brain, resulting in an increased level of cholesterol (CHL) in the mitochondria [244]. Furthermore, Cd exposure promotes lipid peroxidation (LPO), which is mediated by the increased level of oxygen free radicals [245]. The mitochondria are both a storage site for cellular calcium ions and regulators for calcium ion homeostasis. Cd can competitively bind receptors and ion channels that regulate calcium ion influx, modulating calcium-dependent cellular activity [246]. The Ca²⁺/calmodulin-dependent protein kinase II (CaMK-II) regulates cytoskeletal dynamics and apoptotic cell death. Recent advances show that CaMK-II mediates the effects of Cd exposure on actin depolymerization microtubules and cadherin junctions, which are the underlying mechanisms of Cd-induced cytoskeletal disruption and alterations in cellular morphology [246]. Nutritional trace metals, such as Zn and Se, can mitigate Cd-induced mitochondrial toxicity. For example, in a cellular toxicity model of PC12 cells, Cd exposure led to depletion of cellular GSH and oxidative damage to the mitochondria, which can be attenuated by Zn supplementation [247]. Additionally, Se supplementation suppressed Cd-induced oxidative stress and the mitochondrial apoptosis pathway [237].

Mercury is a naturally occurring element that is found in various inorganic and organic forms [248,249]. Both organic and inorganic mercury are neurotoxic. Methylmercury (MeHg) is of special concern as it is an ubiquitous environmental contaminant and its consumption in fish can lead to a devastating neurological disorder, referred to as Minamata disease [250]. Numerous studies have shown that mercury causes brain mitochondrial dysfunction, playing a key role in Hg-induced brain damage and neurological disorders.

As early as 1974, Chang and Hartmann found that mercury was present both in neurons and in glia after MeHg or mercuric bichloride (HgCl₂) administrated to rats orally or subcutaneously [251]. Notably, mitochondria accumulate mercury, mostly because of their abundance of thiol (–SH) groups. Although mercury initiates multiple additive or synergistic disruptive effects, a key mechanism of disruption of mitochondrial function is associated with the production of ROS. HgCl₂ and/or MeHg exposure enhance ROS formation in the CNS, evidenced by both in vivo [252] and in vitro models, including primary rat cortical neuron [253], rat cortical astrocyte [254,255], cerebellar granule neurons and astrocytes [256], and microglia [257], as well as in mixed primary neuron–astrocyte culture [258]. ROS overgeneration leads to consequent oxidative stress [259] and mitochondria-mediated apoptosis. For example, MeHg exposure results in cytochrome c release, caspase-3 and caspase-9 activation, and apoptosis-induced factors (AIF) increase in primary rat cortical neuron [253]. Mitochondria-mediated apoptosis in brain cells is secondary to alteration of mitochondrial membrane potential (MMP) and transition of mitochondrial permeability [260], which have been observed in neuron/astrocyte mixed-culture [258] and astrocyte mono-culture [261,262] after mercury exposure. In addition, the mitochondrial dysfunction evoked by mercury was correlated with damage in mitochondrial bioenergetics. Mercury has been found to act as an inhibitor of the enzymatic activities of mitochondrial respiratory complexes, impairing ATP synthesis in rat hippocampal mitochondria [263]. MeHg exposure reduced GSH levels in astrocytes, increasing the vulnerability to oxidative stress [264]. Apart from a series of biochemical impairments in mitochondria induced by mercury exposure, pathological changes in mitochondrial morphology have also been demonstrated. Li et al. [265] found that a low dose of mercury, lead, and cadmium caused dose-dependent mitochondrial depletion, as well as ridge and matrix dissolution in the hippocampal neurons of rats. Additionally, an in vivo study observed that MeHg induced mitochondrial swelling in the hippocampus of MeHg-exposed F1 generation rats, and enlarged and fused mitochondria in mice cerebral cortex [263].

Dreiem and Seegal [266] found that antioxidant Trolox significantly reduced MeHg-induced ROS, while failing to restore mitochondrial function in rat striatal synaptosomes. The authors revealed that MeHg increased mitochondrial calcium levels, which are fundamental to mitochondrial function. If mitochondria take up too much Ca²⁺, it delays the rise in cytoplasmic Ca²⁺ [267] and the opening of the MPT pore, which may promote the release of cytochrome c and other pro-apoptotic factors, culminating in apoptosis [268]. The modulatory effect of cellular calcium homeostasis by MeHg in mouse spinal motor neurons was also found [269]. In addition, proteomic analysis revealed that many mitochondrial proteins were deregulated by mercury exposure in primary mouse cerebellar granule neuron and astrocytes [256,270], as well as in rat hippocampus [271], thus impairing mitochondrial function associated with cellular metabolism and energy production.

Pb is an environmentally abundant metal pollutant with human exposure mainly through air inhalation and food and water intake. Pb is a strong toxicant for the developmental CNS [272,273]. Pb intoxication in children, even at low doses, is found to impair learning and memory and affect cognitive functions and intellectual development [274,275]. The brain is the primary target of Pb toxicity. Mitochondria play a key role in Pb-induced impairment of nervous system function.

An in vivo study found that the activity or levels of several mitochondrial enzymes were inhibited by Pb exposure. For example, lead acetate (PbAc) exposure in drinking water decreased aldehyde dehydrogenase (ALDH2) expression in brain nucleus accumbens [276], and PbAc exposure from postnatal day 1 (PND1) through PND21 in drinking water of the mother significantly decreased offspring activity of mitochondrial monoamine oxidase (MAO) in all brain regions, including cerebral cortex, hippocampus, and cerebellum, in a dose- and age-dependent manner [277], attributed to the high affinity of Pb for the -SH groups in enzymes, consequently damaging mitochondrial activity and function. In addition, pre- and neonatal exposure to a low dose of Pb (Pb concentration in whole blood < 10 μg/dL) induced synaptic ultrastructural abnormalities in mitochondria including elongated, swollen, and shrunken changes in mitochondria [278], indicating the mitochondrial morphological disruption induced by Pb. Mitochondria-mediated apoptosis has also been shown in Pb-induced neuronal death. PbAc intoxication caused cognitive dysfunction and anxiety-like behavior, along with altered Bax/Bcl-1 expression and increased cytochrome c release from mitochondria in rat brain [279]. In addition, (CH₃COO)₂Pb exposure induced apoptosis via the mitochondrial pathway in embryonic neurocytes isolated from chicken [280]. Similarly, the combined treatment (As+Cd+Pb) in individual lethal concentration (LC)-5 induced a toxic effect on C6-glioma cells derived from rat glioma, via mitochondria-mediated apoptosis, including caspase-9 activation and Bax/Bcl-2 changes [281]. Notably, Zhu et al. found that MPT pore opening plays an important role in Pb-induced neurotoxicity. In SH-SY5Y cells, PbAc exposure significantly impaired mitochondrial function, evidenced by ATP decrease, MMP collapse, ROS production, mitochondrial apoptosis, and morphology changes (swelling and rupture). PbAc treatment significantly increased the protein level of Cyp D, a component of MPT, and induced MPT pore opening in both PC12 and SH-SY5Y cells. Inhibitor of Cyp D significantly reversed mitochondrial damages and cell death induced by Pb [282].

Zinc is an essential trace element that is required for the function of numerous enzymes and DNA-binding transcription factors. Excess zinc influx has been manifested to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases [283,284]. Mitochondria have been identified as targets of the neurotoxic effects of zinc by reducing ATP production and increasing ROS.

Zinc exposure reduced the cellular nicotinamideademine dinucleotide (NAD+) in cultured mouse cortical neurons, followed with a progressive loss of ATP levels and subsequent cell death [285,286,287], indicating the potential inhibition of mitochondrial respiration enzyme. Indeed, several mitochondrial enzymes, including α-ketoglutarate dehydrogenase, NAD+-dependent isocitrate dehydrogenase, succinate dehydrogenase, and cytochrome c oxidase, have been demonstrated to be inhibited by zinc exposure in liver mitochondria [288,289]. Notably, by using bovine heart mitochondria, complex III, specifically the bc 1 complex, was identified as the site of Zn²⁺ binding and inhibition [290,291]. ROS generation has been found to be critical in zinc-induced neurotoxicity, demonstrated in diverse brain cell models [292,293]. As mitochondria are an important source of cellular ROS production, the influx of Zn²⁺ through Ca²⁺-permeable AMPA/kainate channels also triggers rapid mitochondrial depolarization, leading to prolonged production of mitochondrial superoxide in cortical neurons [294].

In addition, several other mechanisms have been involved in the zinc-induced mitochondrial dysfunction. For example, extracellular zinc application stimulates the Ras/MEK/ERK pathway, which leads to zinc-induced mitochondrial dysfunction and consequent cell death in rat neurons [295]. An immediate early transcription factor, egr-1, was found to act downstream of ERK 1/2 to induce neuronal death after zinc exposure [296]. Furthermore, elevated intra-neuronal zinc impairs mitochondrial trafficking without altering morphology, which was restored by PI3k inhibitors, suggesting the role of PI3k activation in zinc-inhibited mitochondrial movement in neurons [295]. Apart from the adverse effects on neurons and glia, zinc overload also critically induced ROS formation in mitochondria and degradation of mitochondrial network in cerebral microvessels, which were mediated through Drp-1-dependent mitochondrial fission pathway, thus contributing to increased permeability of the BBB after cerebral ischemia.

Not only zinc overload, but also zinc defficiency, may impair neurological functions [297] and cause neuronal apoptosis via an intrinsic (mitochondrial) pathway in human neuroblastoma IMR-32 cells and primary rat cortical neurons [298]. Researchers have identified that the transposition of phosphorylated p53 into the mitochondria mediated zinc deficiency-induced mitochondrial alterations and apoptosis in neuronal precursor cell (NT-2 cell line) [299].

Iron is a crucial trace metal for life and is the most abundant transition metal in the brain. It acts as a catalytic center for multiple enzymes and supports many elementary biological processes, including DNA synthesis and repair, oxygen transport, mitochondrial respiration, and neurotransmitter metabolism. Oxidative stress, iron deposition, and mitochondrial dysfunction have been considered as hallmarks of many neurodegenerative diseases, including PD, HD, and AD [300,301], and a positive feedback loop among these three factors seems to exist in neurological disorders.

Upregulation of cellular redox-active iron is directly related to increased ROS and with changes in intracellular reduction potential [302,303]. In the presence of H₂O₂, which is mainly produced by mitochondrial ETC, Fe²⁺ generates hydroxyl radicals (OH) via the Fenton reaction. The hydroxyl radical is considered to be one of the most reactive substances in biological systems because its reaction rate is limited only by its diffusion. This free radical can attack proteins, DNA, and lipid membranes, thus disrupting mitochondrial function and cellular integrity, and eventually leading to oxidative stress and cell apoptosis [304]. Iron overload promotes the production of mitochondrial ROS in SH-SY5Y cells, in an AMP-activated protein kinase (AMPK)-dependent manner [305], and caused ATP production defects, mitochondrial complex I inhibition, and mitochondrial apoptosis in primary cortical neurons [306]. In addition, mitochondria-targeted iron chelators showed protective effects against mitochondrial oxidative damage and neuronal death, both in rotenone-treated SH-SY5Y cells and the dopamine neurons from MPTP-intoxicated mice, which indirectly suggested that iron accumulation in mitochondria induced mitochondrial oxidative damages in neurons and consequent cell death [307]. Moreover, iron overload may induce Drp-1-dependent mitochondrial fragmentation by upregulating intracellular calcium. Lee et al. [308] found that in ferric ammonium citrate (FAC)-stimulated HT-22 hippocampal neuron cells, mitochondria were fragmentated by dephosphorylation of Drp1 (Ser637) and apoptotic neuronal death was increased. Notably, FAC-induced iron overload leads to intracellular calcium elevation and further activation of calcineurin, while inhibition of Ca²⁺ signals related to calcineurin prevents iron overload-induced mitochondrial fragmentation and neuronal cell death. Redox-sensitive ryanodine receptor (RyR)-mediated Ca²⁺ release also was shown to underlie the iron-induced mitochondrial fission in primary hippocampal neurons [309].

Recently, a new iron-dependent programmed cell death, namely ferroptosis, has been found to be a main driver of many neurodegenerative diseases. It is characterized by the accumulation of lipid peroxidation products and lethal ROS derived from iron metabolism and can be pharmacologically inhibited by iron chelators. Although the detailed mechanism by which iron overload promotes ferroptosis has yet to determined, it is reasonable to hypothesize that iron overload may drive the generation of hydroxyl radicals, which further react with liposomes to produce lipid peroxidation products and cause mitochondrial dysfunction, and eventually ferroptosis [310,311,312]. Although mitochondria have been shown to be vital regulators of iron homeostasis and ferroptosis in neurodegenerative diseases [313], more direct evidence targeting iron overload, mitochondrial dysfunction, and ferroptosis is still required. The mitochondria are also the site for the synthesis of iron–sulfur cluster biogenesis (ISCs) and heme prosthetic groups. There is evidence that mitochondrial ISC assembly defects may cause iron overload and consequent negative effects on cellular or mitochondrial function [314,315].

Therefore, iron accumulation induced by direct excessive iron exposure or secondary to iron overload has been demonstrated to play an important role in neurological diseases, via impairing mitochondrial function and inducing oxidative stress. Targeting chelatable iron and the consequent ROS, especially in mitochondria, appear as possible therapeutic options for age-related neurodegenerative conditions [316].

Mn is the 12th most abundant mineral element in the earth crust, and is both nutritionally essential and toxic in excess. Mn is an essential metal for normal growth, development, and cellular homeostasis, as well as a cofactor for multiple enzymes; for example, Mn-superoxide dismutase (Mn-SOD), pyruvate carboxylase, arginase, and glutamine synthase (GS). Manganese preferentially accumulates in tissues rich in mitochondria [317,318], and it is taken up by brain mitochondria via mitochondria Ca²⁺ uniporter [319].

Mn is known to induce mitochondrial dysfunction in the nervous system [320], including the inhibition of the enzymes of the tricarboxylic acid (TCA) cycle in human neuroblastoma (SK-N-SH) and astrocytoma (U87) cells [321] and a reduction in the activities of ETC in rat primary striatal neurons [322] and in PC12 cells [323], ultimately resulting in ATP depletion [324,325,326] and mitochondria-mediated apoptosis [327,328,329]. Notably, these mitochondrial impairments have been found to be rescued by some antioxidants [324,325,330], indicating that oxidative stress is primarily involved in the mechanism of Mn-induced mitochondrial dysfunction.

Another cause of mitochondria-mediated apoptosis induced by Mn exposure is the induction of the MPT [331]. This process causes unrestricted proton movement across the inner mitochondrial membrane, resulting in mitochondrial swelling, mitochondrial membrane potential destruction, further production of ROS, and cellular apoptosis [324,332].