Mitochondrial Stress by Toxic Elements - An Overview

    

    

    Figure 1: Generalized scheme of mitochondrial toxicity by xenobiotics.
    

Structure of mitochondria

Mitochondria consist of a double membrane system in which the MOM surrounds the MIM. The later constitutes the boundary of mitochondrial matrix compartment and contains many folds (cristae) that protrude into this compartment thereby enlarging the MIM surface area. MOM and MIM are separated by the intermitochondrial space and are partially connected via contact sites that are involved in cristae organization. Important structural features of the mitochondrial matrix and cristae system include the Inner Boundary Membrane (IBM), Cristae Junction (CJ) and Cristae Membrane (CM). Maintenance of mitochondrial integrity is important for its function. Further, external, internal morphology and positioning of mT differ amongst cell types and changes over time [12]. Morphological changes in mT are affected by processes viz. fission, fusion, chemiosmosis, physico-chemical properties of MOM and MIM and the nature of extracellular matrix.

Functions of mitochondria

Mitochondria perform several functions. These include regulation of energy production, modulation of redox status, generation of Reactive Oxygen Species (ROS), control of cytosolic Calcium (Ca2+) levels, contribution to cytosolic biosynthetic precursors such as acetyl – coenzyme A and pyrimidines and initiation of apoptosis through activation of Mitochondrial Permeability Transition Pore (MPTP). Xenobiotics can change these functions and affect biosynthetic pathways, cellular signal transduction pathways, transcription factors and chromatin structure to transform a quiescent and differentiated cell into an actively proliferation one.

Morphological plasticity of mT allows mixing of its contents, redistribution of damaged proteins and lipids, local functioning of the subsets of mT within the cell and mitophagy. mT can not be generated de novo [13]. Therefore, mT fission is crucial to allow their inheritance during cell division. Transcellular exchange of individual mT via nanotubular structures (nanotunnelling) has been demonstrated under certain conditions [14]. mT DNA can be transferred between cells by extracellular vesicles [15].

Mitochondrial homeostasis

The maintenance/regulation of mitochondrial structure and function has been studied by a number of workers. Mitochondrial fission and fusion proteins significantly contribute to mT homeostasis. These processes are mediated by microRNAs that function as negative regulators for gene expression. They can inhibit mRNA translation or promote mRNA degradation [16]. Irreparable mT are removed by fusion, fission, autophagy or biogenesis. Damaged mT are removed either by general autophagy or priming of mT for selective autophagic recognition [17,18]. Certain protein receptors viz. autophagy related protein (Atg 32) in yeast; Nix/BCL2 interacting protein 3 like (Bnip3l), BCL2 interacting protein 3 (Bnip3) and FUN 14 domain containing 1 (Fundc1) in mammalian systems directly act in autophagy. mT can make multiple copies of their genome, however, lack nucleotide excision pathway. Therefore, DNA damaged by environmental chemicals is removed via mitochondrial fusion, fission, autophagy and biogenesis [19]. Principally, mitochondrial fusion and fission are considered as key processes in mitochondrial stress response and morphological changes in mitochondria [20].

Cellular export processes viz exocytosis may help in removing the damaged mT. Recent researches show that multiple signalling mechanisms i.e. nucleotides, biosynthetic intermediates, peptides, mT ROS, cardiolipin, mT unfolded protein response, reduced AMP/ ATP ratio and calcium release are also involved in mT homeostasis [21-23].

Ca²⁺ plays a regulatory role in mT physiology [24]. mT can import Ca²⁺ through a uniporter, energized by an electrochemical gradient. ER membranes associated with mT bring ER type 3 Inositol Triphosphate Receptor (IP3R) Ca²⁺ release channels into juxtaposition with mT Ca²⁺ uninporter.

Defining mitochondrial stress

Many patho-physiological conditions or exposure to drugs/chemicals can cause mitochondrial dysfunction. These include metabolic disorders [25], cancer [26], diabetes [27] and neurodegenerative diseases [28]. Proper mitochondrial function in mammals requires -1200 genes {Mito carta 2.0) and (Mitominer 4.0{ [29]. Only a small fraction of proteins is encoded in the mitochondrial DNA. A variety of chemicals/ drugs/ xenobiotics can disturb mT function by generating stress. Exposure of organisms to chemicals can cause mutations in mT DNA [30]. In turn, these mutations increase the sensitivity of mT to stress [31,32]. Stress can alter the morphology of mT [20].

In general, xenobiotics affect mT by inhibiting electron transfer. For instance, many herbicides and pesticides affect respiratory chain. While rotenone inhibits Complex –I, antimycin inhibits complex – III. Carbon monoxide, azide and cyanide bind to heme a³ of complex IV, thereby inhibiting the oxidase activity. Most important, mT DNA encodes 13 proteins of the respiratory chain. Since mT DNA possesses no protective proteins, ROS easily damage mTDNA. Mutations in mTDNA generate dysfunctional proteins essential for respiratory chain, thus inhibiting the electron flow. Inhibition of the electron flow results into accumulation of reduced ubiquinone and reduced cytochrome C. Finally, reduced ubiquinone, complex I and complex III donate electrons directly to oxygen generating superoxide anions (O₂^.-). ROS activate caspase pathway leading to apoptosis. Reduced ATP production (metabolic stress) activates autophagy.

Another group of xenobiotics are classified as energy transfer inhibitors. For example oligomycin inhibits ATP synthase. It reduces proton flow from the inter-membrane space to the matrix. Thus energy transfer inhibitors generate ROS.

Third category is known as uncouplers. Uncoupling is the state in which ATP synthase is inhibited by disruption of pH gradient. For example 2, 4 –Dinitrophenol (DNP) and Pentachlorophenol (PCP) are known as uncoupling agents. These compounds inhibit the production of ATP leading to metabolic stress. Metabolic stress induces autophagy. It activates p38 c-Jun N terminal Kinase (JNK) pathway. These pathways collectively lead to apoptosis, necrosis and mitophagic cell death.

Mitochondrial stress by environmental xenobiotics

Mitochondrial toxicity by drugs is better known than environmental pollutants. There were speculations that like drugs, environmental agents might also target mT [33]. Nonetheless, only a few studies demonstrated analogy between the effects of drugs and environmental toxins. Effects of paraquat, a pesticide, are similar to that of adriamycin that act by redox cycling [34]. While rotenone inhibits complex I, carbon monoxide and cyanide act as complex IV inhibitors [35]. Others that manifest their toxicity through mitochondria include particulate matter [36]; PAH quinines [37]; methoxychlor [38]; and pentachorophenol [39]. Many of these xenobiotics affect primary targets other than mT and thus effects on mT become secondary to these effects.

Mitochondrial stress by toxic elements

Amongst toxic elements, cadmium and copper [40]; manganese and lead [41]; arsenic [42] and mercury [43] have been demonstrated to cause toxicity through mT dysfunction/involvement. However, promising research on their effects on mT is wanting. This review focuses mainly on mT stress induced by toxic elements and presents directions for future research.

Cadmium (Cd)

mT represents key target organelle in cadmium Cd) intoxication. Exposure to Cd can cause different changes in mT viz. morphological changes; alterations in mT membrane permeability and potential; generation of ROS; mutation in mTDNA; altered gene expression and apoptosis. Biochemical mechanisms responsible for cadmium toxicity have been studied in a variety of in vitro and in vivo models [44]. It inactivates sulfydryl groups of essential proteins. It can cause functional changes in nucleus, mitochondria and endoplasmic reticulum [45,46]. Its effects on OXPHOS are considered as key factors affecting its toxicity [47]. The uncoupling effect of Cd on OXPHOS could be due to the acceleration of H⁺ influx through the Pi/H⁺ symporter [48]. Heat shock protein₆₀ (Hsp₆₀) mostly resides in mitochondrial matrix. Its over expression might exert a protective role assisting the cell in refolding and processing of damaged proteins [49]. Certain reports show that Cd affects mitochondrial electron transport chain by impairing electron flow through the cytochrome bc1 complex [50]. Cadmium can induce morphological changes too in mT. It could decrease the number of mT in the kidney of rat. Further, degenerated mT with reduced matrix density and loss of cristae were also observed [51]. Changes in the permeability of MIM caused opening of MPTP [52-54]. Exposure to cadmium is known to induce a massive accumulation of ROS [55]. These reactive species affect mT membrane potential and activate consequent events leading to apoptosis [56]. A quick survey of available literature showed that there were about 500 studies dealing with the effects of Cd on mT. Most of them dealt with indirect involvement of Cd in mitochondrial injury. A few reports dealt with the amelioration of mT dysfunction by treatment with antioxidants. It has now been accepted that Cd affects mT function through oxidative stress [57].

The role of Cd induced mTDNA mutations in neoplastic tissue formation is yet to be established. Cd is known to affect mT gene expression [58]. It upregulates HSP₆₀ in HB2 cells [59]. The over expression of HSP₆₀ may be protective or it can regulate programmed cell death [60].

Thus sufficient experimental evidence suggests mitochondrial participation in Cd induced cytotoxicity. Disruption in mT membrane permeability, generation of ROS and oxidative stress predominantly contribute to its toxic effects.

Mercury (Hg)

Mercury is a direct enzyme poison. It binds to sulfydryl, phosphoryl, carboxyl, amide and amine groups of proteins. On binding with mercury, these proteins become inactive. Inorganic and organic forms of mercury exhibit selective toxicity in organisms. Elemental mercury being lipid soluble can cross cell membranes and disrupt their structure and function. Organo -mercurials are classified as long chained aryl mercury compounds and short chained alkyl mercury compounds. Short chained alkyl compounds viz. methyl mercury are highly toxic [61].

The earliest report that suggested mT damage by mercury was published by Donaldson [62] who showed that moderate levels of mercuric chloride (200-300ppm) given to chicks in drinking water over an 8 week period adversely affected the integrity of mT membrane. Subsequently, it was shown by Sone et al. [63] that Me-Hg induced mT swelling. Stimulation of ATPase and energy dependent H⁺ extrusion were equally dependent upon K⁺. Its uptake by mT and the resulting loss of membrane potential was the major cause of uncoupling. Iida [64] studied the effects of various organic mercury compounds on OXPHOS in rat liver mT. While studying immunotoxic effects of methylmercury, it was demonstrated that methylmercury kills human lymphocytes by inducing apoptosis. It increased mT transmembrane potential (Ψm) and generated ROS that activated cell death signalling pathways [65]. Oxidative stress mechanisms were reported to alter mT activity in human THP1 monocytic cells exposed to Hg (II) in a dose dependent manner [66]. Further, effects of Me-Hg on mitochondrial function were found to be age dependent. Me-Hg reduced mitochondrial function as assessed by MTT reduction and mT membrane potential in the synaptosomes of early post-natal rats than those of greater age [67]. Mercury induced diseases like Multiple Sclerosis (MS) have also been associated with mitochondrial damage. Repeated administration of Hg induced mT swelling, generation of ROS, collapse of mitochondrial membrane potential and cytochrome c release [68]. In vitro studies made by Ma et al. [69] on mT isolated from Wistar rat liver confirmed that Hg²⁺ changes mT structure, causes mT swelling, alters mT membrane potential and membrane fluidity and influences cytochrome c release. mT were found to play a crucial role in neuronal apoptosis induced by Me-Hg. Observations made on primary cultured neurones after exposure to 0,0.25; 0.5; or 1μM Me-Hg for 1-6 hr respectively showed that Me-Hg induced neuronal apoptosis through ER and mT pathways. Results on caspase-3’ caspase-9 and cytochrome C release indicated disruption of mT dysfunction. Recently, diabetogenic effects of metals viz. Cd, Hg, Pb and Mo has been attributed to bioenergetic disruption of mT [70].

Information detailed above confirms that cell death signalling pathways are activated by Hg. Increase in transmembrane potential, enhanced generation of ROS, release of cytochrome c and activation of caspases are involved in its cytotoxicity.

Lead (Pb)

Lead is an ubiquitous element. It is known to cause serious health effects in man and animals. Lead has been found to cause anaemia in number of cases. It inhibits porphirobilinogen synthase and ferrochelatase preventing the synthesis of porphobilinogen and heme synthesis. It may cause ineffective synthesis and subsequently microcytic anaemia. Further, it blocks voltage dependent calcium channels. It does lead to encephalopathy and impaired respiratory function.

A few studies show its effects on mitochondria. It affects Ca²⁺ handling by heart mitochondria [71]. Glycine cleavage in rat liver mitochondria was also decreased by lead [72]. It was found to affect the structure and function of rat liver mT [73]. Synaptosomal fraction of the brain of a fresh water cat fish Clarius batrachus demonstrated increased generation of reactive oxygen species, decrease in protein thiols and Na⁺ , K⁺ ATPase activity and mitochondrial electron transport chain after exposure to 37.8 and 75.6mg/L for 20, 40, and 60 days [74]. Lead could cause mutations in mT DNA. This hypothesis was tested in yeast, Saccharomyces cerevisae by Sousa and Soares [75]. These workers attributed these effects to oxidative stress induced by lead. It has now been confirmed that Pb affects mT respiratory complex. This effect is the outcome of oxidative stress and MPT that lead to cell death signalling via opening of MPTP and cytochrome c release [76].

In brief, mitochondrial toxicity caused by lead includes its bindings with thiols, inhibition of Na⁺ K⁺ dependent ATPases, mutation in mT DNA and oxidative stress.

Copper (Cu)

Copper (Cu) is an essential transition element. It is a co-factor for many enzymes viz. Cu/Zn superoxide dismutase; cytochrome c oxidase; dopamine β hydroxylase and monoamine oxidase. Although mechanisms of copper toxicity are not completely understood, it has been implicated in the pathogenesis of neurodegenerative disorders i.e. Alzheimers’ disease; Parkinsons’ disease; familial amyotrophic lateral scelerosis and prion disorders. It binds with disease causing proteins viz. A-B peptide, a sinuclein and prion protein. This binding results into generation of free radicals and associated events of oxidative stress. Elevated tissue levels of copper have been associated with an autosomal recessive inherited disorder known as Wilsons’ disease (hepatolenticular degeneration).

Role of mT in Cu induced cell injury has been studied by a few scientists. Reddy et al. [77] demonstrated that MPTP, oxidative stress and nitrosative stress play a major role in Cu induced toxicity in astrocytes. However, alterations in MPT had no contribution in its neural toxicity. Further, copper mediated oxidative stress is known to contribute to mT dysfunction which is considered as a major cause of neurodegeneration. In conditions of copper deficiency also, decreased activity of cytochrome c oxidase leads to mT dysfunction Role of Cu in neurodegenerative processes was further elaborated by Arnal et al. [78]. This group of scientists studied the effects of Cu and / or cholesterol on mT function in Wistar rats. Cu⁺ induced a higher cholesterol/phospholipid ratio in mT membrane with a simultaneous decrease in glutathione content. Concentration of peroxidation products, conjugated dienes and lipid peroxides increased. These workers concluded that Cu and cholesterol potentiate the neurodegenerative process. Mitochondrial Cu homeostasis especially in Wilson disease patients was reviewed by Zischka and Einer [79]. This study concluded that Cu overlaod causes structural, biophysical and biochemical deficits during Wilsons’ disease. Involvement of mT in copper induced oxidative stress and apoptosis was studied in chicken hepatocytes by Yang et al. [80]. Dose dependent increase in ROS levels, MDA, NO, SOD; decrease in GSH and upregulation of Bax, Bak1, Cyt c and apoptosis attributed these effects to changes in mT pathways. Briefly, Cu induced mT changes viz. nitrosative stress, opening of MPTP and oxidative stress promote cell death.

Arsenic (As)

Arsenic is historically known to inhibit cellular respiration and cause mitochondrial injury. Arsenic induced Reactive Oxygen Species (ROS) cause genetic mutations and cancer by promoting DNA damage, activating oncogenic kinases and activating lipids and proteins that inactivate DNA repair mechanisms.

It was hypothesized that mT, in particular the mT DNA are important targets of mutagenic effects of arsenic in mammalian cells. Partridge et al [81]. showed that arsenic did not induce nuclear mutations in mT DNA depleted cells. These authors showed that arsenic alters mT function by decreasing cytochrome c oxidase functions. Further, another study showed that arsenic alters mT DNA and telomere length in individuals possessing different arsenic metabolizing capacity [82]. In arsenic induced neurotoxicity also, mT oxidative stress and dysfunction were implicated [83]. Arsenic induced oxidative stress was linked to decreased mT biogenesis in rat liver. mT biogenesis was evident by decreased protein and mRNA expression of Nuclear Respiratory Factor (NRF-1), Nuclear Respiratory Factor 2 (NRF-2), peroxisome proliferator activator receptor γ co-activator 1 a(PGC-1a) and mitochondrial Transformation factor A (Tfam) in arsenic treated rat liver. Thus increased oxidative stress was found to be associated with decreased mT biogenesis. Arsenic induced neural damage in chicken was also found to be associated with oxidative stress and disruption in mT dynamics. Upregulation of Autophagy Related Genes (ATGs) was also observed [84]. Involvement of mT functions was demonstrated in female rats fed on sodium arsenate (2-4mg/kg body weight). Chandravanshi et al. [85] reported that increased oxidative stress and apoptosis in frontal cortex, hippocampus and corpus striatum of developing rats could be attributed to changes in mT function. Impairment of neurohormones, oxidative stress and mT dysfunction express synergistic behaviour during arsenic toxicity. Medda et al. [86] showed that arsenic directly affects cortex, cerebellum and microglial cells by inducing pro-inflammatory cytokines viz. TNF-a, IL-6. Mitochondrial dysfunction has been implicated in the toxic effects of arsenic on spermatogonia. ATO damaged mT structure i.e mT cristae and mT vacuolar degeneration [87].

Certain reports indicate that antioxidants protect arsenic induced mT toxicity. Pace et al. [88] have identified 21 mitoprotective antioxidants that can effectively reverse mT dysfunction. Earlier reports suggest a protective role of ascorbic acid against arsenic induced mT toxicity [89]. Taken together, mT DNA damage, cytochrome c release and upregulation of autophagy related genes are important contributors of its cytotoxicity.

Chromium (Cr)

Chromium (Cr) is an important industrial metal. The stable oxidation states of Cr are trivalent chromium (Cr^III) and hexavalent Chromium (Cr^VI). It can enter the body through different portals i.e. inhalation, ingestion and absorption through skin. Cr^VI can enter the cell through anion transporters. Inside the cell, it can be reduced to lower oxidation states viz. pentavalent Chromium (Cr^V), and tetravalent Chromium (Cr^IV). It has been generally agreed that ROS plays a key role in Cr induced cytotoxicity. Experimental evidence indicates that Cr^VI affects Mitochondrial Respiratory Chain Complex I (MRCC I) to induce ROS [90]. MRCC I appears to be the new target and a new mechanism involved in Cr^VI induced apoptosis. Several metals might induce toxicity through MRCC (I-V) and disrupt the mT membrane structure and function [91]. Role of mT biogenesis in Cr induced hepatotoxicity in human liver cells was studied by Zhong et al. [92]. It was demonstrated that mT biogenesis, comprising the mT DNA copy number and mT mass was significantly increased HepG2 cells after exposure to low concentration of Cr. Moreover expression of genes related to mT function complex I and complex V was upregulated at low concentration of Cr^VI. mRNA and protein levels of key transcriptional regulators of mT biogenesis viz. the peroxisome–proliferator-activated receptor γ coactivator-1a (PGC- 1a), NRF-1 and mitochondrial Transcription Factor A (TFAM) were also increased by low concentration of Cr^VI in HepG2 cells. Contrarily, high concentration of Cr^VI inhibited mT biogenesis [92]. Depletion of mitochondrial membrane potential in skin fibroblasts ScSF cells of Indo-Pacific hump back dolphin (Sousa chinensis) after exposure to Cr^VI was reported by Yu et al. [93]. This effect was attributed to decrease in ATP level, cytochrome c release from mT and the activation of caspase -9. Results of Cr^III may not support those obtained from Cr^VI. An in vitro study made in RAW 264.7 murine macrophages after exposure to 50-150 ppm Cr^III exhibited no mT dysfunction. A recent report from Seydi et al. [94] showed that Cr^VI caused Mt Membrane Potential (MMP) collapse in isolated human lymphocytes. In brief, a surge in the generation of ROS, inhibition of mT respiratory chain complex I and activation of caspase 9 mediate its effects on cell death.

Nickel (Ni)

Toxicity/ carcinogenic potential of nickel compounds has now been established. They are known to cause oxidative stress, genotoxicity, dermal and neurotoxicity. Role of mT in its toxicity has been studied by a few workers. Bemba-Meka et al. [95] reported that Ni3S2 induced changes in mT membrane potential in human lymphocytes in a dose and time dependent manner. These changes were mediated by oxidative stress. Antioxidants like N-acetyl cysteine inhibited the changes in mT membrane potential. Another study from Xu et al. [96] also confirmed that oxidative stress induced by nickel contributes in its neurotoxic effects. Melatonin, which is known to possess antioxidative properties inhibited neurotoxicity of Ni in mouse neuroblastoma cell lines (neuro2a) and cortical neurones. Oxidative damage to mT DNA might account for neurotoxicity of nickel. mT DNA nucleoid structure could also be affected by Ni. Xu et al. [97] confirmed that Ni could reduce mT DNA content and mT DNA transcripts. It decreased protein levels of Tfam, a key protein component of nucleoid organization. However, melatonin pretreatment attenuated oxidative damage to mT DNA. Protective effects of taurine, an antioxidant and essential for mT function, against Ni induced neurotoxicity have also been reported by the same group of scientists ( Xu et al. Maiti et al. [98,99] attributed neurotoxicity of Ni induced in a cat fish, Clarius batarchus L. to inhibition of ATPase activity and mT respiratoty chain dysfunction. These studies emphasize the role of mT in nickel induced neurotoxicity.

Role of calcium in mitochondrial stress

Many xenobiotics impair mT function employing Ca²⁺ dependent signalling pathways [100,101]. Fleckenstein et al. for the first time showed that entry of the excess Ca²⁺ in cardiomyocytes manifests cardiac pathology after ischemia. Intracellular compartmentalization of Ca²⁺ occur in mT. Increased generation of ROS facilitate changes in MPT that promote cell death [102]. It has been reported that mT in many pathological conditions accumulate Ca²⁺ that is subsequently released along with other matrix solutes [103]. Oxidative stress and impaired Ca²⁺ homeostasis both contribute to mT mediated cell death [104]. Thus MPT remains to be the major mechanism of causing mT failure. It can lead to necrosis due to ATP depletion or to apoptosis due to caspase activation. However, further studies are needed to establish the role of specific elements on Ca²⁺ mediated mitochondrial permeability transition.

Conclusion and Future Perspectives

Mitochondrial biology remains central to our understanding on cell death and related mechanisms [105]. It offers a platform for interdisciplinary research on the aetiology of many complex diseases as well as ageing process. Though impressive research on mT dysfunction have been reported during last decades, many issues related to its dysfunction in different pathological conditions are yet to be resolved. A few of these include- elucidating the modulation of specific OXPHOS genes, mitochondrial hormesis, DNA methylation , mT- nuclear DNA interaction, retrograde signalling and adaptive mechanisms during cellular insult by toxic elements. Further, Antioxidant Responsive Elements (ARE) are to be identified. Detailed studies on fusion and fission of mT, induced by toxic elements are also awaited. There exists convincing evidence that certain signalling molecules known as mitokines may be secreted during mitochondrial stress. They may be proteins involved in retrograde signalling [106]. Further work is warranted to decipher the role of mitokines in metal toxicity. Finally, lack of inter-mitochondrial communication and quality control process in a pathologic state may play an important role in mT dysfunction. Efforts made by World Mitochondrial Society deserve appreciation. Next (12^th in the series) Berlin Congress proposed in Oct. 2021 is expected to add more information to our present knowledge on mitochondria.

Acknowledgement

Author is thankful to Indian Science Congress Association, Kolkata for awarding him Sir Asutosh Mookerjee Fellowship (no. 73/2020-2021). The technical assistance received from Ms Huma and Ms Meenu Singh is gratefully acknowledged.

References

1. Wallace DC. Why do we have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. 2007; 76: 781-821.
2. Lane N, Martin W. The energetics of genome complexity. 2010; 467: 929- 934.
3. Ernester JA, Schatz G. Mitochondria: a historical review. 1981; 91: 227-255.
4. Noguchi M, Kashahara A. Mitochondrial dynamics control cell differentiation. Biochem Biophys Res Commun. 2018; 500: 59-64.
5. Frieden M, Arnaccdeau S, Castelbou C, DEmaurex N. Subplasmalemal mitochondria modulate the activity of plasma membrane Ca2+ ATPase. 2005; 280: 43198-43208.
6. Buck MD, O’Sullivan D, Klein Geltink RI. Mitochondrial dynamics control T cell fate through metabolic programming. 2016; 166: 63-76.
7. Basit F, vanOppen LM, Schockel L. Mitochondrial complex I inhibition triggers a mitophagy dependent ROs increase leading to necroptosis and ferroptosis in melanoma cells. 2017; 8: e2716.
8. Gottlieb E, Armour SM, Harris MH. Mitochondrial membrane potential regulates matrix configuration and cytochrome C release during apoptosis. 2003; 10: 709-717.
9. Spiropoulos J, Turnball DM, Chinnery PF. Can mitochondrial mutations cause sperm dysfunction? 2002; 8: 719-727.
10. Venkatesh S, Deecaraman M, Kumar R, Shamshi MB, Dara R. Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mT DNA) mutations in male infertility. 2009; 129: 127-137.
11. Kang Y, Fielden LF, Stojanorski D. Mitochondrial protein transport in health and disease. 2018; 76: 142-153.
12. Collins TJ, Bootman MD. Mitochondria are morphologically heterogenous within cells. 2003; 206: 1993-2000.
13. Shiota T, Traven A, Lithgow T. Mitochondrial biogenesis: cell cycle dependent investment in making mitochondria. 2015; 25: R78-R80.
14. Rustom A, Saffrich R, Markovie I, Walther P, Gercles HH. Nanotubular highways for intercellular organelle transport. 2004; 303, 1007-1010.
15. Sansone P, Savini C, Kurelac I, Chang Q, et al. Pachaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy inhormonal therapy resistant breast cancer. 2017; 114: E9066-E9075.
16. Lee Y, Ahn C, Han J, Choi H et al. The nuclear RNAse III Drosha initiates microRNA processing. 2003; 425: 415-419.
17. Wang K, Klionsky DJ. Mitochondria removed by autophagy. 2011; 7: 297- 300.
18. Liu Y, Zhou J, Wang L et al. A cyanine dye to probe mitophagy: simultaneous detection of mitochondria and autolysosomes in live cells. 2016; 138: 12368- 12374.
19. Bess AS, Crocker TL, Ryde IT, Meyer JN. Mitochondrial dynamics and autophagy aid in removal of persistent mitochondrial DNA damage in Caenorhabditis elegans. 2012.
20. Meyer JN, Chan SSL. Sources, mechanisms and consequences of chemical induced mitochondrial toxicity. 2017; 391: 2-4.
21. Giorgi C, MIssiroli S, Petergnani S. Mitochondria associated membranes: composition, molecular mechanisms and physic-pathological implications. 2015; 22: 995-1019.
22. Quiros PM, Mottis A, Aurierx J. Mitonuclear communication and homeostasis and stress. 2016; 17: 213-226.
23. Bohorynch I, Khalimonchuk O. Sending out an SOS: mitochondria as a signalling. 2016; 4: 109.
24. McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. 1990; 70: 391-425.
25. Koopman WJ, Willems PH, Smeitink JA. Monogenetic mitochondrial disorders. 2012; 366: 1132-1141.
26. Alirol E, Martinous JC. Mitochondria and cancer: Is there a morphological connection? 2006; 25: 4706-4716.
27. Rovira-Llopis S, Banuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha Mand Victor VM. Mitochondrial dynamics in type – 2 diabestes: Pathophysiological implications. 2017; 11: 637-645.
28. Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. OXPHOS mutations and neurodegeneration. 2013; 32: 9-29.
29. Wiedenann N, Pfanner N. Mitochondrial machineries for protein import and assembly. 2017; 86: 685-714.
30. Valente WJ, Ericson NG, Long AS, White PA, Marchetti F, Biclas JH. Mitochondrial DNA exhibits resstance to induced point and deletion mutations. 2016; 44: 8513-8524.
31. Chan SSL. Inherited mitochondrial genomic instability and chemical exposures. 2017; 391: 75-83.
32. Luz AL, Godebo TR, Smith LL, Lenthner TC, Maurer LL, Meyer JN. Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability. 2017; 387: 81-94.
33. Shaughnessy DT, Worth L, Jr Lawler CP, McAllister KA, LOnley MJ, Copeland WC. Meeting report: Identification of biomarkers of early detections of mitochondrial dysfunction. 2010; 10: 579-581.
34. Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinsons’ disease. 2012; 16: 920-934.
35. Ninomiya-Tsuji J. Mitochondrial dysfunction. In “Molecular and Biochemical Toxicology. 2008; 319-332.
36. Janssen BG, Munters E, Pieters N. 2012. Placental mitochondrial DNA content and particulate air pollution during life. 2012; 120: 1346-1352.
37. Biswas G, Srinivasan S, Anandatheerthavarda HK. Dioxin mediated tumor progression through activation of mitochondria-to-nucleus stress signalling. 2008; 105: 186-191.
38. Gupta RK, Schuh RA, Fiskum G, Flaws JA. Methoxychlor causes mitochondrial dysfunction and oxidative damage in mouse ovary. 2006; 216: 436-445.
39. Valmas N, Zuryn S, Ebert PR. Mitochondrial uncouplersact synergistically with fumigant phosphine to disrupt mitochondrial membrane potential and cause cell death. 2008; 252: 33-39.
40. Garceau N, Pichaud N, Couture P. Inhibition of goldfish mitochondrial metabolism by exposure to Cd, Cu and Ni. 2010; 98: 107-112.
41. Bowman AB, Kwakye GF, Hernandez EH, Aschner M. Role of manganese in nerurodegenerativ e diseases. 2011; 25: 191-203.
42. Echaniz-Laguna A, Benoilid A, Vinzio S. Mitochondrial myopathy caused by arsenic trioxide therapy. 2012; 119: 4272-4274.
43. Belyaeva EA, Sokolova TV, Emelyanova LV, Zakharova IO. Mitochondrial electron transport chain in heavy metal induced neurotoxicity: effects of cadmium, mercury and copper. 2012; 136063.
44. Rana SVS. Metals and apoptosis-recent developments. 2008; 22: 262-284.
45. Diep PTN, DEnizeau F, JUmarie C. Kinetics of the early subcellular distribution of cadmium in rat hepatocytes. 2005; 18, 255-267.
46. Rana SVS. Endoplasmic reticulum stress by toxic elements- review of recent developments. 2020; 196: 10-19.
47. Belyaeva EA, Korotkov SM. Mechanisms of primary Cd2+ induced rat liver mitochondrial dysfunction: discrete modes of Cd2+ on calcium thiol dependent domains. 2003; 192: 56-68.
48. Koike H, Shinohara Y, Terada H. Why is inorganic phosphate necessary for uncoupling of oxidative pjosphorylation by Cd²⁺ in rat liver mitochondria? 1991; 1060: 75-81.
49. Qui J, GAO HQ, Liang Y, Yu H, Zhou RH. Comparative proetomics analysis reveals role of heat shock proteins 60 in digoxin induced toxicity in human endothelial cells. 2008; 1784: 1857-1864.
50. Miccadei S, Floridi A. Sites of inhibition of mitochondrial electron transport by cadmium. 1993; 89: 159-167.
51. Takebayashi et al. 2000.
52. Korotkov SM, Skulski IA, Glazunov VV. Cd2+ effects on respiration and swelling of rat liver mitochondria were modified by monovalent cations.1998; 70: 17-23.
53. Zazueta C, Sanchez C, Garcia N, Correa F. Possible involvement of the adenine nucleotide translocase in the activation of the permeability transition pore induced by cadmium. 2000; 32: 1093-1109.
54. Belyaeva HEA, Dymkowska D, Wieckowski MR, Wajtezak L. Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. 2008; 231: 34-42.
55. Cannino G, Feruggia E, Liparello C, Rinaldi A. Effects of cadmium chloride on some mitochondrial related activity and gene expression of humanMDAMB231 breast tumor cells. 2008; 102:1668-1676.
56. Chatterjee S, Kundu S, Bhattacharya. Mechanisms of cadmium induced apoptosis in the immunocyte. 2008; 177: 83-89.
57. Pavon N, Buelna-Chontal M, Marcias-Lopez A, et al. On the oxidative damage by cadmium to kidney mitochondrial functions. 2019; 97: 187-192.
58. Sirchia R, Longo A, Luparello C. Cadmium regulation of apoptotic and stress response genes in humoral and immortalized epithelial cells of the human breast. 2008; 90: 1578-1590.
59. Cannino G, Ferrugia E, Rinaldi AM. Proteins participating to the post transcriptional regulation of the mitochondrial cytochrome c oxidase subunit IV via elements located in the 3’UTR. 2009; 9: 471-480.
60. Chandra D, Choy G, Tang DG. Cytosolic accumulation of HSP60 during apoptosis with or without mictochodrial release: evidence that its proapoptotic or prosurvival functions involve differential interactions with caspase 3. 2007; 282: 31289-31301.
61. ATSDR (Agency for Toxic Substances and Disease Registry). 1995.
62. Donaldson WE. The effects of mercury ingestion on hepatic mitochondrial membrane of chicks. 1976; 55, 2280-2284.
63. Sone N, Larsstuvold MK, Kagawa Y. Effect of methylmercury on phosphorylation, transport and oxidation of mammalian mitochondria. 1977; 82: 859-868.
64. Iida Y. Studies on oxidative and phosphorylative systems in mitochondria II. studies on the effects of various organic mercury compounds and heavy metals on rat liver mitochondria. 1978; 33: 417-425.
65. Shenker BH, Guo TL, Shapiro IM. Low level methyl mercury exposure causes human T cells to undergo apoptosis: evidence of mitochondrial dysfunction. 1998; 77: 149-159.
66. Messer RLW, Lockward PE, Tseng WY, Edwards K, et al. Mercury II alters mitochondrial activity of monocytes at sublethal doses via oxidative stress mechanisms. 2005; 75.
67. Dreiem A, Gertz CC, Seegal RF. The effects of methyl mercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes is age dependent. 2005; 87: 156-162.
68. Kahrizi F, SAlimi A, Noorbaksh F, et al. Repeated administration of mercury intensifies brain damage in multiple sclerosis through mitochondrial dysfunction. 2016; 15: 834-841.
69. Ma L, Bi K, Fan Y, Jiang Z. et al. modulation of mercury induced rat liver mitochondrial dysfunction. 2018; 7: 1135.
70. Elmorsy E, Al-Ghafni A, Al-Doghaither H, Ghulam J. Effects of environmental metals on mitochondrial bioenergetics of CD-1 mice pancreatic B cells. 2021; 70.
71. Parr DR, Harris EJ. The effect of lead on the calcium handling capacity of rat heart mitochondria. 1976; 158: 284-294.
72. Suketa Y, Yamanaka N, Yamamoto T. Effect of lead on glycine cleavage activity in rat liver mitochondria. 1976; 2: 25-29.
73. Wielgus-Serafinska E, Zawadzka A, Falcus B. The effect of lead acetate on rat liver mitochondria. 1980; 31: 659-668.
74. Maiti AK, Saha HC, Paul G. Effect of lead on oxidative stress, Na⁺ K⁺ ATPase activity and mitochondrial electron transport chain activity of the brain of Clarius batrachus L. 2010; 84: 672-676.
75. Sousa CA, Soares EV. Mitochondria are the main source and one of the targets of lead induced oxidative stress in the yeast Saccharomyces cerevisae. 2014; 98: 5153-5160.
76. Ma L, Liu JY, Dong JX, Xizo Q, Zhao J, Jiang FL. Toxicity of Pb2+ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition. 2017; 6: 822-830.
77. Reddy PVB, Rama Rao KV, Norenberg MD. The mitochondrial permeability transition and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured nerurones and astrocytes. 2008; 88: 816-830.
78. Arnal N, Castillo O, deAlaniz MJT, Marra CA. Effect of copper and/or cholesterol overload on mitochondrial function in a rat model of incipient neurodegeneration. 2013.
79. Ziscka H, Einer C. Mitochondrial copper homeostasis and its derailment in Wilsons’ disease. 2018; 102: 71-75.
80. Yang F, Pei R, Zhang Z, et al. Copper induces oxidative stress and apoptosis through mitochondria mediated pathway in chicken hepatocytes. 2019; 54: 310-316.
81. Patridge MA, Huang SXL, Rosa EH, Davidson MM, Hei TK. Arsenic induced mitochondrial DNA damage and altered mitochondrial function: implications for genotoxic mechanisms in mammalian cells. 2007; 67: 5239-5247.
82. Ameer SS, Xu Y, Engstrom K. Exposure to inorganic arsenic is associated with increased mitochondrial DNA copy number and longer telomere length in peripheral blood. 2016.
83. Prakash C, Soni M, Kumar V. Mitochondrial oxidative stress and dysfunction in arsenic neurotoxicity: a review. 2016; 36: 179-188.
84. Liu Y, Zhao H, Wang Y et al. Arsenic (III) and /or copper (II) induces oxidative stress in chicken brain and subsequent effects on mitochondrial homeostasis and autophagy. 2020; 211: 111201.
85. Chandravanshi LP, Gupta R, Shukla R. Developmental neurotoxicity of arsenic: involvement of oxidative stress and mitochondrial functions. 2018; 186: 185-198.
86. Medda N, Patra R, Ghosh TK, Maiti S. Neurotoxic mechanisms of arsenic: synergistic effects of mitochondrial instability, oxidative stress and hormonal neurotransmitter impairment. 2020; 198: 8-15.
87. Chen H, Liu G, Qiao N. Toxic effects of arsenic trioxide on spermatogonia are associated with oxidative stress, mitochondrial dysfunction, autophagy and metabolomic alterations. 2020; 190.
88. Pace C, Dagda R, Angermann J. Antioxidants protect against arsenic induced mitochondrial cardiotoxicity. 2017; 5: 38.
89. Singh S, Rana SVS. Ascorbic acid improves mitochondrial function in liver of arsenic treated rats. 2010; 26: 265-272.
90. Xiao F, Li Y, Dai L, et al. Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species dependent caspas-3 activation in L-02 hepatocytes. 2012; 30: 629-635.
91. Ghasemi H, Rostampour F, Ranjbar A. The role of oxidative stress in metals toxicity/mitochondrial dysfunction as key players. 2014; 3: 2-13.
92. Zhong X, Silveria-e Su, Zhong C. Mitochondrial biogenesis in response to chromium (VI), toxicity in human liver cells. 2017; 18: 1877.
93. Yu X, Yu R, Gui D, et al. Hexavalent chromium induces oxidative stress and mitochondria mediated apoptosis in isolated skin fibroblasts of Indo Pacific humpback dolphin. 2018; 203: 179-186.
94. Seydi E, Mahzani F, ZArei MH, et al. Hexavalent chromium induced oxidative stress and toxicity in isolated human lymphocytes. 2020; 3.
95. M’Memba-Meka P, Lemieux N, Chakranarti SK. Role of oxidative stress, mitochondrial membrane potential and calcium homeostasis in nickel subsulfide induced human lymphocyte death. 2006; 369: 2134.
96. Xu S, He MD, Zhong M, et al. Melatonin protects against nickel induced neurotoxicity by reducing oxidative stress and maintaining mitochondrial function. 2010; 49: 86-94.
97. Xu S, He MD, Lu YH, et al. Nickel exposure induces oxidative damage to mitochondria DNA in neuro2a cells: the neuroprotective role of melatonin. 2011; 51: 426-433.
98. Xu S, He MD, Zhing M, et al. The neuroprotective effects of taurine against nickel by reducing oxidative stress and maintaining mitochondrial function in cortical neurones. 2015; 590: 52-57.
99. Maiti AK, Saha NC, Paul G, Dhara K. Mitochondrial respiratory chain inhibition and Na+ K+ ATPase dysfunction are determinant factors modulating the toxicity of nickel in brain of cat fish,Clarius batrachus L. 2018; 11: 306-315.
100. Trump BF, Berezcsky IK. Calcium mediated cell injury and cell death. 1995; 9: 219-228.
101. Fleckenstein A, Janke J, Doring HJ, Leder O. Myocardial fibre necrosis due to intracellular Ca overload – a new principle in cardiac pathophysiology.1974; 4: 563-580.
102. Orrenius S, Gogvadze V, Zhivotvsky B. Mitochondrial oxidative stress: implications for cell death. 2007; 47: 143-183.
103. Rana SVS. Protection of metal toxicity by melatonin-recent advances. 2018; 6: 851-864.
104. Hunter DR, Haworth RA. The calcium induced membrane transition in mitochondria. III Transitional Ca2+ release. 1979; 195: 468-477.
105. Rana SVS. Mechanistic paradigms of cell death – revisited. 2021; 42: 913- 917.
106. Gottlieb RA, Mentzer RM, Linton PJ. Impaied mitopjagy at the heart of injury. 2011; 7: 1573-1574.