Role of mitochondria and mitochondrial transplantation in drug-induced toxic organ injury

Mitochondria are crucial organelles within eukaryotic cells, responsible for generating adenosine triphosphate (ATP) through oxidative phosphorylation. They play a significant role in maintaining cellular homeostasis, managing cell death pathways such as apoptosis and necrosis, and acting as the primary site for reactive oxygen species (ROS) production. This intricate relationship with cellular functions makes mitochondria central to the study of drug-induced toxic organ injuries, where mitochondrial dysfunction is a key mechanism of harm.

Mitochondrial dysfunction can arise from various drug-induced mechanisms, including the inhibition of respiratory complexes within the electron transport chain (ETC), disruption of cellular bioenergetics, induction of oxidative stress, and interference with mitochondrial DNA (mtDNA) replication and protein synthesis. These mechanisms contribute to adverse effects in tissues such as the liver, kidneys, and heart.

1. Respiratory Complex Inhibition: Drugs can inhibit complexes within the ETC, leading to reduced ATP production and increased ROS generation. This oxidative stress can damage mitochondrial and cellular structures, contributing to cell death via apoptosis or necrosis. For instance, non-steroidal anti-inflammatory drugs (NSAIDs) and certain antibiotics have been shown to disrupt the function of complex I and III, respectively.
2. Oxidative Stress: Elevated ROS levels, often due to impaired ETC function, can cause significant damage. For instance, clofibrate, used to treat hyperlipidemia, increases ROS production by uncoupling oxidative phosphorylation at complex II or III, resulting in mitochondrial damage. Oxidative stress not only impairs mitochondrial function but also affects cellular proteins, lipids, and nucleic acids, leading to widespread cellular damage.
3. DNA Replication Interference: Some drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs) like Zidovudine, inhibit mtDNA polymerase γ, impairing mtDNA replication and leading to conditions such as hepatic steatosis, pancreatitis, lactic acidosis, nephrotoxicity, and peripheral neuropathy. The disruption of mtDNA replication affects the synthesis of essential mitochondrial proteins, compromising mitochondrial function and cellular energy production.
4. Calcium Homeostasis Disruption: Certain drugs can alter mitochondrial calcium homeostasis, leading to mitochondrial permeability transition pore (mPTP) opening, further contributing to mitochondrial dysfunction and cell death. For example, anthracyclines used in chemotherapy can disrupt calcium signaling, exacerbating mitochondrial damage and cardiotoxicity.

The liver, kidneys, and heart are particularly vulnerable to drug-induced mitochondrial toxicity due to their high metabolic activity and roles in drug metabolism and excretion.

• Liver: Drug-induced liver injury (DILI) is a leading cause of acute liver failure and liver-related deaths, often resulting from mitochondrial dysfunction caused by various medications. Acetaminophen overdose, for instance, leads to the formation of toxic metabolites that impair mitochondrial respiration and induce oxidative stress, causing hepatocyte death and liver failure.
• Kidneys: Acute kidney injury (AKI) from nephrotoxic drugs is common, with mitochondrial damage playing a pivotal role. This damage impairs the kidneys' ability to maintain homeostasis and regulate the extracellular environment. Aminoglycoside antibiotics and chemotherapeutic agents like cisplatin are known to cause mitochondrial dysfunction in renal tubular cells, leading to nephrotoxicity.
• Heart: The heart, relying heavily on aerobic metabolism, is susceptible to mitochondrial dysfunction from cardiotoxic drugs, affecting its energy production and leading to myocardial injury. Doxorubicin, a widely used chemotherapeutic agent, induces cardiotoxicity by generating ROS and disrupting mitochondrial function, ultimately leading to cardiomyopathy and heart failure.

Mitochondrial transplantation has emerged as a promising therapeutic strategy for mitigating drug-induced toxic organ injuries. This technique involves transferring healthy mitochondria into damaged cells to restore mitochondrial function and improve cellular health. Research indicates potential benefits in various conditions, including ischemic tissue damage and neurodegenerative diseases.

In preclinical studies, such as those by Kubat et al., mitochondrial transplantation has shown positive effects in models of drug-induced nephrotoxicity. For example, in a doxorubicin-induced nephrotoxicity model, isolated mitochondria from mesenchymal stem cells were injected into the renal cortex of rats, demonstrating protective effects against kidney damage. This approach has also been explored in cardiac models, where mitochondrial transplantation helped to preserve myocardial function and reduce infarct size after ischemia-reperfusion injury.

While mitochondrial transplantation shows great promise, several challenges must be addressed to advance this therapy to clinical practice. These include optimizing mitochondrial isolation and delivery methods, ensuring mitochondrial survival and integration within recipient cells, and overcoming potential immune responses. Additionally, the long-term safety and efficacy of mitochondrial transplantation need thorough investigation through clinical trials.

Future research should focus on understanding the mechanisms underlying successful mitochondrial transplantation and identifying the most effective protocols for different types of organ injuries. Advances in bioengineering and nanotechnology may also contribute to the development of more efficient and targeted mitochondrial delivery systems.

The increasing prevalence of drug prescriptions and over-the-counter medications has heightened the exposure to drug-induced toxicities. Mitochondrial dysfunction is a central mechanism underlying these toxicities, making it a critical focus for research. Mitochondrial transplantation offers a novel therapeutic avenue, with the potential to mitigate toxic damage and improve patient outcomes. Further research is essential to refine this technique, understand its mechanisms, and develop effective clinical protocols.

In conclusion, the role of mitochondria in drug-induced toxic organ injury underscores the need for continued exploration of mitochondrial transplantation. This promising approach holds the potential to transform treatment strategies for drug-induced injuries and improve the quality of life for affected patients.

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https://www.xiahepublishing.com/2472-0712/ERHM-2022-00117

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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