Introduction
Mitochondria play a crucial role in the homeostasis of eukaryotic cells by generating adenosine triphosphate (ATP) via oxidative phosphorylation. Additionally, mitochondria are closely related to cell death pathways, such as apoptosis and necrosis, which are significant factors in toxic tissue damage. Moreover, mitochondria are the main base of reactive oxygen species (ROS) production, which occurs as a result of ATP production. The amount of mitochondrial ROS (mtROS) depends on the calcium load, metabolic status, and the use of substrates by mitochondria. When mitochondrial dysfunction occurs, an increase in mtROS production can cause oxidative damage to cellular structures. However, mtROS plays a role in important processes such as immune function, basic developmental processes, and antioxidant defense mechanisms.1
There are various mechanisms related to mitochondria that cause drug-induced toxic damage. Inhibition of the mitochondrial electron transport chain (ETC), ROS production, reduction of protein synthesis, cytochrome c secretion, and cell death are some of these mechanisms.2 Apoptosis is the energy-dependent cell death pathway. Cytochrome c is released from the mitochondrial intermembrane space in the initial step of the mechanism (intrinsic pathway). It can also be initiated by apoptosis caspases (extrinsic pathway). Necrosis is an uncontrolled mechanism for cell death, caused by external factors such as hypoxia, trauma, and infection, which then cause swelling of the cell organelles, plasma membrane rupture, and cell lysis.3,4 There is a close relationship between apoptosis and necrosis in terms of signaling pathways and regulatory mechanisms. For instance, some toxins can damage membrane structures and cause the release of cytochrome c and interrupt mitochondria processes. Some drugs target mitochondria as their area of therapeutic action. For example, a group of anticancer drugs can result in mitochondrial toxicity in cancer cells.5 Mitochondrial damage that occurs in the mitochondria of healthy cells for this or other reasons can lead to undesirable results and yield toxic effects.
This review aims to summarize the role of mitochondria in toxic organ damage and the therapeutic effects of mitochondrial transplantation. We provide an overview of the mitochondrial mechanisms of toxic organ damage, with a focus on some of the most commonly damaged organs such as liver and kidney, and the potential of mitochondrial transplantation.
Drug induced mitochondrial toxicity
Various chemical agents, whether toxic or therapeutic, exert significant effects on mitochondrial bioenergetic mechanisms by interacting with the ETC and causing changes in oxidative phosphorylation processes. As a result of these effects, the electrochemical proton gradient and electron transport mechanisms may be disrupted, the effectiveness of ATP production may be decreased, and oxidative damage may occur. In addition, changes in deoxyribonucleic acid (DNA) replication and protein expression can also bring important results. Some of the main sites of action of various chemical agents are listed in the table below (Table 1).6,7
Table 1Examples of the effects of drugs on mitochondria6,7
| Inhibitors of the Respiratory Chain (Complex I) | Group I, NADH-flavin interface inhibitor (e.g., rhein); Group II, quinol antagonists (e.g., myxothiazol and quinolone aurachins); Group III, specific/potent complex I inhibitors (e.g., rotenone) |
| Inhibitors of the Respiratory Chain (Complex III) | Group I occludes ubiquinol oxidation (e.g., myxothiazol, strobilurins, and oudemansins); -Group II occludes electron transfer and prevents the reduction of cytochrome bL (e.g., undecylhydroxydioxobenzothiazole and undecylhydroxynaphtoquinone); Group III prevents electron transfer between heme bH and quinone molecules (e.g., antimycin A and funiculosin, quinolones) |
| Inhibitors of the Respiratory Chain (Complex IV and Cytochrome c Oxidase) | Group I inhibits heme-binding enzymes (e.g., azide, cyanide, and sulfide); -Group II inhibits COX enzyme via oxygen competition (e.g., carbon monoxide and nitric oxide); Group III inhibits COX enzyme via cytochrome c binding (e.g., polycations); Group IV, other inhibitors not interacting with heme groups (e.g., phosphate ions and alkaline pH) |
| Inhibitors of ATP-Synthase (H+-ATP synthase (complex V) | Inhibits ATPase activity and occludes proton transmission (e.g., mycotoxins, flavonoids and local anesthetics) |
| Uncouplers of Oxidative Phosphorylation | Affects routine mitochondrial energy production function: Lipophilic weak acids (e.g., substituted phenols, trifluoromethyl benzimidazoles, salicylanilides, carbonyl cyanide phenylhydrazones); Other types of uncouplers (e.g., ionophore gramicidin, cationic uncoupler pentamidine, membrane-active peptide mastoparan) |
| Targeting mtDNA | Interfere with mtDNA and mtDNA processes: Effects mitochondrial polymerase-γ (e.g., menadione, antiviral drugs); Effects mitochondrial ribosomal RNA (e.g., chloramphenicol, thiamphenicol); Effects mitochondrial topoisomerases (e.g., amsacrine, etoposide, teniposide) |
There are various mechanisms related to mitochondria that cause drug-induced toxic damage. Inhibition of the ETC is one of these mechanisms that can cause excessive ROS production and cytochrome c secretion. Many drugs and drug metabolites can inhibit the ETC. Metformin is used to control hyperglycemia in type 2 diabetes and inhibits complex I of the ETC.8 The inhibition effect of metformin was shown in a study on complex I isolated from metformin-pretreated hepatocyte mitochondria. According to the result, metformin localized in complex I and inhibited the mitochondrial respiratory chain but did not affect the other oxidative phosphorylation mechanisms.9 Although the mechanisms are not identified, it is reported that the binding of the hydrocarbon part of the biguanide molecule to the hydrocarbon molecules of the membrane phospholipids could be a mechanism.2 Inhibition of complex I activity brings about a reduction of hepatic gluconeogenesis and an augmentation of glucose consumption in peripheral tissue.10 Rotenone, widely used as a pesticide, is a toxic agent that inhibits mitochondrial respiratory complex I. Rotenone prevents electron transfer from iron-sulfur to ubiquinone, inhibits oxidative phosphorylation and ATP synthesis, as well as induces ROS production.4 It is also reported that rotenone caused the death of HL-60 cells via apoptosis revealed by DNA fragmentation, cytochrome c release, and caspase 3 activation.11 Another drug that acts on an ETC complex is antimycin A. Antimycin A is an antibiotic that binds to a domain of cytochrome b on complex III, blocking the electron transport from bH heme to ubiquinone. This can result in increased ROS production and cell death by releasing iron from ferritin.12,13
Drugs can bind membrane phospholipids and inhibit oxidative phosphorylation via changes in membrane permeability. 2,4-Dinitrophenol disrupts the mitochondrial membrane potential, transmits protons through the mitochondrial membrane into the mitochondrial matrix, and uncouples oxidative phosphorylation. As the proton gradient and complex V activities are disrupted, protons need to be transported through the enzyme to synthesize ATP which results in thermal energy production without ATP formation.14 Although it is not legal today, it is used by bodybuilders because it causes an increase in metabolism and the loss of body fat. Tolcapone, an inhibitor of levodopa metabolism, is also a potential uncoupling drug that decreases cellular ATP.8 In a study on isolated mitochondria, GABA receptor agonist propofol (2,6-diisopropylphenol) has been shown to reduce transmembrane potential.15 Although it can cause an increase in oxygen uptake and glycolysis, it can decrease glucose synthesis and cause lactic acidosis.
Oxidative stress is a defined mechanism of drug toxicity. For instance, the antibiotic doxorubicin is used as a chemotherapeutic drug that arrests cell proliferation via induction of DNA damage. However, it can cause cardiotoxicity via oxidative stress, impairment of mitochondria, down-regulation of cardiac-specific genes, and myocyte apoptosis.16 Semiquinone radicals generated by nicotinamide adenine dinucleotide (NAD)+hydrogen (H) (NADH):b5 reductase and complex I are reported as a cause of mitochondrial dysfunction and impaired oxidative phosphorylation.2 Moreover, semiquinone reacts with oxygen, generates superoxide and hydrogen peroxide, and forms a complex with iron molecules, producing hydroxyl radical, which is one of the most reactive free radical.17 Oxidative stress is reported to be a mechanism behind the inhibition of adenine nucleotide translocase and the deterioration of calcium homeostasis in a study performed on isolated mitochondria.18 These changes cause mitochondrial permeability transition, cytochrome c release, and caspase activation, resulting in apoptosis. Necrosis is another cell death mechanism by ATP loss in doxorubicin toxicity. Clofibrate, used for hyperlipidemia treatment, also increases ROS production and causes oxidative damage to mitochondria. The reason for ROS production is defined as the uncoupling of oxidative phosphorylation at either complex II or III.19
Some drugs can also affect mitochondrial DNA replication. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI; e.g., Zidovudine) which are used to interrupt the replication of HIV can inhibit mitochondrial DNA polymerase γ activity. NRTI-induced mitochondrial toxicity is related to clinically hepatic steatosis, pancreatitis, lactic acidosis, nephrotoxicity, and peripheral neuropathy.20 Inhibition of mitochondrial DNA replication may cause a decrease in mitochondrial DNA (mtDNA).21 As mtDNA encodes some mitochondrial proteins, mitochondrial function is deleteriously affected. A NRTI-induced cytotoxic effect on human hepatoma cells was reported in a study in which increased levels of mitochondrial ROS, DNA oxidation, and complex I inhibition were revealed.22
Toxic organ damage
The liver, kidney, and heart are the organs where damage due to toxic dose drug intake is frequently encountered. Most drugs are metabolized and removed by the liver and kidney, making them the most susceptible to toxic damage. Drug-induced liver injury (DILI) is the most common reason for acute liver failure in the US and the foremost cause of liver-related death in Western countries.23,24 DILI is reported as a reason for 10% of hospitalizations with abnormal liver function.25 The kidney is an indispensable organ that executes numerous vital functions containing the preservation of homeostasis, regulation of the extracellular environment, and excretion of metabolites.26 Exposure to drugs frequently results in drug-induced acute kidney injury (AKI).27 The frequency of drug-induced nephrotoxicity is reported in approximately 14–26% of adults with AKI cases, but it can be as high as 60%.28–30 In addition, drug-induced toxic damage is seen primarily in organs such as the heart, which uses aerobic pathways in energy production.
Mitochondrial functions are significantly dependent on maintaining the impermeable structure of the inner mitochondrial membrane and mitochondrial complex function. At the same time, mtDNA, which is unique to the mitochondria, should be healthy, and its replication and the interaction between mtDNA and cell DNA should be appropriate. Many drugs have been reported to cause toxic damage due to their damaging effects on mitochondrial function, mtDNA, and protein expression. These effects of drugs on mitochondria are important for the prevention and treatment of toxic drug damage as well as for the development of new drugs and the evaluation of drug efficacy, as reported by Dykens et al.31
Liver
Wide-ranging agents can cause liver damage, like antibiotics, nonsteroidal anti-inflammatory drugs, anesthetics, anticancer drugs, central nervous system agents, and antiretrovirals.32,33 The toxic effects of these agents, that can cause tissue damage and liver failure leading to organ transplantation or death, are reported in plenty of studies.34–40 The mechanisms of DILI are not fully described, but mitochondrial dysfunction containing membrane permeabilization, oxidative phosphorylation (OXPHOS) impairment, fatty acid oxidation inhibition, and mtDNA depletion are reported as significant mechanisms, besides many other events.41,42 Drugs themselves or reactive metabolites of the drugs generated in the cell can cause mitochondrial dysfunction,43,44 but the transformation of nontoxic active ingredients into a chemically reactive metabolite is the most common source of DILI. Conjugation of these metabolites with glutathione (GSH) and hepatic macromolecules (including mitochondrial membranes) harms the cell and causes hepatic damage.44
Drugs can cause impaired respiration and energy production through different mechanisms. OXPHOS uncoupling and inhibition of the mitochondrial respiratory chain activity (together or separately) are some of these mechanisms.45–47 Blocking of electron flow decreases ATP formation and impairs OXPHOS which harms cell function and survival. Severe ATP depletion can impair calcium homeostasis and consecutively activate proteases, endonucleases, and phospholipases that take part in the devastation of cell structures.48 It is reported that liver cell necrosis, cholestasis, and fibrosis can occur consequently in some cases.49 Impairment of mitochondrial respiration gives rise to the accumulation of electrons in the mitochondrial respiratory chain which causes ROS formation, oxidative stress, and mtDNA damage. Blocking of electron flow can also result in lactic acidosis because of the insufficient reduction of pyruvate.42 The event that led to this situation is a decrease in the reoxidation of NADH into oxidised nicotinamide adenine dinucleotide (NAD+). Oxidation of pyruvate by the pyruvate dehydrogenase complex decreases because of the relative deficiency of NAD+.
Some drugs can inhibit the mitochondrial fatty acid oxidation and consequently induce microvesicular steatosis.50 The existence of cytoplasmic lipid droplets is presented in liver pathology.51 This was reported as a potential severe liver lesion that can be associated with liver failure.52 Antiestrogenic tamoxifen which is used to treat breast cancer accumulates electrophoretically in mitochondria, inhibits OXPHOS and mitochondrial β-oxidation, and can cause steatosis as well.53,54 Tamoxifen can also lead to progressive hepatic mtDNA depletion and inhibits mitochondrial ATPase.55,56 Another mechanism that leads to steatosis is the activation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Inhibition of mitochondrial respiration causes a decrease in ATP and an increase in adenosine diphosphate and adenosine monophosphate (AMP). When AMP increases, AMPK activates, and ATP-consuming pathways shift to ATP-producing catabolic pathways.57 AMPK activation stimulates fatty acid uptake via the fatty acid transporter and enhances fatty acid oxidation. In case of a lack of NAD+, efficient β-oxidation might be prevented and contributes to fat accumulation in hepatic cells.58
Another cause of cell death and liver damage is mitochondrial permeability transition pore (MPTP) opening. MPTP opening is one of the important mechanisms of mitochondrial membrane disruption that can be a result of toxicity activated by reactive drug metabolites. Some of the mechanisms of MPTP opening are oxidation of MPTP components, increased levels of mitochondrial calcium, and activation of c-Jun N-terminal kinase or other endogenous MPTP inducers.46,59,60 Opening of MPTP causes proton and fluid accumulation within the organelle, causing both loss of function and activating cell death pathways.61 It has been reported that some drugs like salicylate, benzarone, and valproic acid can uncouple mitochondrial respiration and trigger MPTP opening.62–66 Excessive intake of acetaminophen can also cause MPTP opening throughout hepatic GSH depletion, mitochondria damage, ROS formation, and c-Jun N-terminal kinase activation.67,68
Kidney
Toxic dose drug intake can cause a group of renal diseases including acute renal injury, altered intraglomerular hemodynamics, interstitial nephritis, acid-base and electrolyte disorders, and inflammatory changes in tubular cells that cause AKI and renal scarring.30 The kidney is highly dependent on ATP to sustain its function, such as secretion and reabsorption of solutes.69 For this reason, mitochondrial ATP production is crucial for the kidney, and ATP production in mitochondria is oxygen-dependent. Principally, the proximal and distal tubular cells are rich in mitochondria.70 Moreover, the proximal tubular cells also have plenty of transporters (e.g., solute carrier and ATP binding cassette pumps) which carry drugs between peritubular blood and the urine.71
The damage to mitochondrial membranes, mitochondrial complexes, and mitochondrial DNA, the disruption of protein synthesis and ATP production, and the increase of MPTP are some of the toxic damage mechanisms.72 Inhibition of protein synthesis and mitochondrial DNA replication has been demonstrated in drug-related acute kidney injury experiments. One study reported that streptozotocin damaged mitochondrial DNA in a dose-dependent manner in rat insulinoma cell lines.73 Another study on four different cell lines (HEK293, HeLa, Hepa 1-6, and GT1-7) found that tetracyclines caused mitonuclear protein imbalance by influencing nuclear gene expression and mitochondrial translation as well as changing mitochondrial dynamics and function.74 Inhibition of DNA polymerase γ (responsible for replication of the mitochondrial genome) activity is a mechanism of acyclic nucleotide analog-induced acute kidney injury.75 Covalent modifications of mtDNA might result in the inhibition of mitochondrial DNA replication. Additionally, cisplatin shows toxic effects via the covalent binding of the platinum derivates to mtDNA.76 Mitochondria are considered an endosymbiotic organelle of bacterial origin. Therefore, mitochondrial protein synthesis is the target of some antibiotics.77
Mitochondrial complexes especially, complex I and complex II, are the target for a wide range of drugs.78 Ifosfamide, a chemotherapeutic, was reported as a cause of tubular dysfunction.79 Activation of complex I of rat renal cortex mitochondria was found to decrease in a study after ifosfamide treatment.80 Antibiotic gentamicin can directly interact with complex II, and it can inhibit mitochondrial protein synthesis.81,82 Moreover, it was reported that antibiotic vancomycin inhibited complex I activity and depolarized the mitochondrial membrane of the Lilly Laboratories Culture-Porcine Kidney 1 cells.83
Mitochondrial damage can be related to the direct interaction of taxane or platinum with the permeability transition pore. The platinum-containing drug cisplatin can generate crosslinks with the voltage-dependent anion channel and ease membrane permeabilization. As a consequence, cytochrome c releases, and apoptotic cell death occurs.84 Paclitaxel is another drug that induces mitochondrial permeability transition pore opening and alters mitochondrial dynamics and function.85,86 It induces an abrupt fall of the mitochondrial membrane potential and a loss of mitochondrial calcium ions (Ca2+). The renal tubule epithelial lining and brush border membranes diminish because of necrosis and apoptosis.87 Furthermore, aristolochic acid causes ATP depletion, depolarization of the mitochondrial membrane, the release of cytochrome c, activation of caspase 3 in HK-2 cells, and inhibition of the mitochondrial adenine nucleotide translocase in isolated mitochondria.88–90
Mitochondrial transplantation
Mitochondria play an important role in damage mechanisms due to toxic dose drug intake. Against this damage, protective mechanisms in mitochondria and adaptation of mitochondria to changed conditions gain importance.91 For example, the production of mitochondrial antioxidants increases in response to augmented oxidative stress.92 Additionally, heat shock proteins, peroxisome proliferator receptor gamma coactivator 1 (PGC-1), nuclear factor-kappa, and mitochondrial biogenesis also increase.92,93 Because PGC-1 controls mitochondrial biogenesis via induction of nuclear respiratory factors 1 and 2, synthesis of respiratory chain polypeptides and induction of mitochondrial transcription factors rise.94 Although mtDNA has many copies, it also has its weaknesses, such as the lack of a nucleotide excision repair mechanism. However, they can provide the elimination of damaged mtDNA through mechanisms such as mitochondrial fusion, fission, and autophagy.1
Mitochondria serve an important role in research, particularly in the process of drug-induced toxic damage and the time after the damage. Positive effects of mitochondrial transplantation have been reported not only in drug intoxication but also in many disease models such as ischemic tissue damage and neurodegenerative diseases. In this context, it has been discussed in more detail in our review articles.95,96 In contrast, there are few studies on the effects of mitochondrial transplantation on tissue damage caused by the intake of toxic dose drugs (Table 2).82,97–100 Kubat et al. investigated the effects of mitochondrial transplantation isolated from mesenchymal stem cells on a doxorubicin-mediated nephrotoxicity model within rats and its mechanism of action. They carried out kidney injury with an intraperitoneal injection of 6 mg/kg doxorubicin and transplanted the isolated mitochondria to the renal cortex of rats via direct injection. Histopathological (hematoxylin-eosin staining), immunohistochemical (Bcl-2 and caspase-3), biochemical (urea, creatinine, and blood urea nitrogen), and oxidative stress analysis (lipid peroxidation, total superoxide dismutase, and glutathione peroxidase) were performed in the study. It was reported that mitochondrial transplantation improved the cellular antioxidant capacity and the regeneration of tubular cells. Protein accumulation in tubular cells and renal deficits were decreased. Moreover, Bcl-2 levels increased while caspase-3 levels decreased. As a result of this study, mitochondrial dysfunction and doxorubicin-mediated nephrotoxicity were interrelated, and transplanting isolated mitochondria to damaged tissue had therapeutic effects.97
Table 2Summary of the effect of mitochondrial transplantation in different drug toxicity methods
| Target cell/tissue | Toxic damage method | Toxic effects of drugs | Application route and dose | Effects of transplanted mitochondria | Ref. |
|---|
| a. Liver | a. Intraperitoneal injection of 250 mg/kg APAP | a. Liver damage and cell swelling, increased transaminase activities and ROS production, decreased ATP and GSH levels | a. Intravenous injection of 1012 mitochondria | a. Reduced hepatotoxicity, decreased transaminase activities, increased ATP and GSH levels, and reduced ROS production | 98 |
| b. Hepatocyte cell culture | b. Incubation of 10 mM APAP for 2 h | b. Decreased cell viability | b. Coincubation of 10 μg/mL mitochondria | b. Increased cell viability, increased, ATP and GSH levels, decreased ROS production, and anti-apoptotic effects | 98 |
| Kidney | Intraperitoneal injection of 6 mg/kg DOX | Increased tubular dilatation and tubular protein accumulation, increased caspase-3, and decreased Bcl-2 levels | Direct injection of 8×106/ml mitochondria into the kidney | Increased tubular cell regeneration, improved renal deficits, reduced apoptosis, and oxidative stress | 97 |
| Liver | Subcutaneous injection of 1 µl/kg 20% carbon tetrachloride 1 time over 3 days for 3 weeks | Decreased cell viability, increased MDA, reduced antioxidants and ATP levels, enhanced serum ALT and AST levels, impaired tissue morphology, mitochondrial swelling, broken mitochondrial membrane, irregular crista arrangement, and vacuolar structure | Systemic injection of 0.2 or 0.4 mg/kg/day mitochondria for 7 days | Higher cell viability, increased anti-oxidants and ATP levels, reduced ROS production, decreased serum ALT and AST levels, improved tissue morphology and reduced fibrotic area, and improved mitochondrial ultrastructure and membrane potential | 100 |
| Liver | Oral administration of 1 g/kg APAP | Increased hepatocyte necrosis, ballooning degeneration, and inflammatory and apoptotic cell levels, elevated serum AST, ALT, and LDH levels, and increased oxidant levels | Injection into the subcapsular region of the spleen of 8.2 × 106 mitochondria | No evidence of tissue damage, reduced apoptotic cells, normal AST, ALT, and LDH levels, and decreased oxidant levels | 99 |
| Renal proximal tubular cells | Incubation of 1.5 mM gentamicin for 2 h | Increased cytotoxicity, ROS production, MMP collapse, LPO content, GSSG levels, and caspase-3 activity and reduced levels of ATP and GSH | Coincubation of 0.5 mg of mitochondrial protein/ml | Decreased cytotoxicity, ROS production, MMP collapse, LPO content, GSSG levels, and caspase-3 activity and increased levels of ATP and GSH | 82 |
Shi et al. studied an acetaminophen (APAP) toxicity model applied by intraperitoneal injection of 250 mg/kg APAP on mice.98 They demonstrated in vivo distribution of transplanted mitochondria via systemic injection and reported that the injected mitochondria were internalized by several tissues, such as the brain, lung, liver, kidney, and muscle. They reported the reduction of serum transaminase, histopathological damage, mitochondrial swelling, ROS production, and promotion of hepatic GSH and ATP levels after mitochondrial transplantation. The results were reported as indicators of the therapeutic effects of transplanted exogenous mitochondria.98
Ulger et al. examined the effects of transplanted mitochondria on APAP-induced toxic liver damage. 8.2×106 isolated mitochondria were transplanted to the liver after induction of tissue damage with 1 g/kg APAP administered by oral gavage to the rats. They investigated multiple effects of the transplanted mitochondria. These were hepatocyte necrosis, ballooning, and degeneration, and the presence of inflammatory cells as shown by histological analysis; apoptosis as shown by terminal deoxynucleotidyl transferase dUTP nick end labeling assay; AST, ALT, lactate dehydrogenase (LDH) levels in blood samples; and malondialdehyde (MDA), superoxide dismutase, total antioxidant status, total oxidant status, and GSH levels as shown by oxidative stress analysis. According to the results, histological structures of damaged liver tissue improved to a similar level with healthy rats. Additionally, plasma ALT levels, apoptotic cells, and total oxidant levels decreased. It was reported that mitochondrial transplantation was very effective in terms of histological and functional improvement.99
Future directions
Mitochondrial transplantation is an emerging research area that draws attention with significant results in current studies and attracts more attention day by day. Ischemic tissue injuries and neurodegenerative diseases are frequently studied models of disease. In addition, as explained in the previous section, there are successful results in experimental studies on drug-induced toxic damage. Considering the mechanisms of action of drugs on mitochondria, it can be thought that, by transplanting healthy mitochondria to damaged tissues, eminent progress can be made in this area where significant problems are experienced during treatment. However, there are some limitations and problems that need to be resolved before the mitochondrial transplantation method can be used most effectively. For example, it has been reported that the presence of isolated mitochondria in a medium containing Ca2+ may adversely affect mitochondrial function and energy production. It is claimed that Ca2+ will accumulate in the mitochondria and increase membrane permeability. In this case, it is thought that osmotic balance agents in the mitochondrial medium may enter into the mitochondria and cause organelle edema. In addition, the fate of mitochondria after penetrating the target cell (how many mitochondria can pass into the cell and how they maintain their integrity and functions) is another question. Moreover, it is necessary to determine what the consequences will be when the mitochondrial genetic material interacts with the cell nucleus and how the immune reactions will respond following mitochondrial transplantation.95,101 For the clinical application of mitochondrial transplantation, these questions should be answered and issues, such as the route of administration and dosing, should be investigated with multi-faceted studies, and protocols should be clearly stated.
Studies have been conducted in different research areas based on the role of mitochondria in drug-induced toxic organ damage. In this context, mitohormesis is a phenomenon that interests scientists. While stress normally has detrimental effects, mitohormesis refers to the potential of stress to be beneficial at low levels. For instance, although exercise increases ROS production, it can have curative effects on mitochondrial function and patients. In addition to exercise, the mitohormetic effects of different manipulations such as dietary restriction, genetic manipulation, and reduction of ROS levels are emphasized. It has been reported that the severe genetic knockdown of ETC components decreases lifespan in Caenorhabditis elegans, but mild genetic knockdown increases viability.1,102 It is an extremely important and necessary issue for today’s world to conduct research on effective treatment by using this and other research methods and to support such research.
Conclusions
Nowadays, the increase in the number of prescriptions and the upsurge in the use of over-the-counter drugs has led to more exposure to toxic-dose drug usage. Although mitochondria are components for many physiological mechanisms in cells, they have a significant role in toxic organ damage mechanisms. The large number of drugs that cause mitochondrial dysfunction increasingly attracts the attention of researchers. Many drug failures or withdrawals have been reported related to mitochondrial toxicity. For this reason, some of the cellular damage mechanisms might be blocked via reorganizing the mitochondrial processes by transplantation of isolated healthy mitochondria to the damaged tissue. In light of the data obtained from studies on mitochondria transplantation, more research is needed on this method, which has the potential to have significant effects on toxic drug damage.
Abbreviations
- AKI:
acute kidney injury
- ALT:
alanine transaminase
- AMP:
adenosine monophosphate
- AMPK:
5′ adenosine monophosphate-activated protein kinase
- APAP:
acetaminophen
- AST:
aspartate aminotransferase
- ATP:
adenosine triphosphate
- Ca2+:
calcium ion
- DILI:
drug-induced liver injury
- DNA:
deoxyribonucleic acid
- ETC:
electron transport chain
- GSH:
glutathione
- LDH:
lactate dehydrogenase NAD+, oxidised nicotinamide adenine dinucleotide
- NADH:
nicotinamide adenine dinucleotide (NAD)+hydrogen (H)
- NRTIs:
nucleotide reverse transcriptase inhibitors
- MDA:
malondialdehyde
- mtDNA:
mitochondrial DNA
- mtROS:
mitochondrial ROS
- MPTP:
mitochondrial permeability transition pore
- OXPHOS:
oxidative phosphorylation
- PGC-1:
peroxisome proliferator receptor gamma coactivator 1
- ROS:
reactive oxygen species
Declarations
Funding
The authors declare that there was no funding associated with this publication.
Conflict of interest
The authors have no conflicts of interest related to this publication.
Authors’ contributions
Concept/design (OU and GBK). Drafting of the manuscript (GBK and OU). All authors read and approved the final manuscript.