Impaired Mitochondrial Structure and Function in Disease

More than just the powerhouse of the cells, mitochondria are responsible for antioxidant defence, regulating redox balance and inflammation, and play a key role in the process of healthy ageing.^1,2 When mitochondrial function is compromised, however, they contribute to the production of reactive oxygen species (ROS), which in turn causes damage not only to the mitochondria, but the rest of the cell³ (Figure 1). One mechanism by which mitochondrial ‘machinery’ can become damaged is under conditions of ROS overload and/or excessive calcium (Ca2+) uptake, triggering the opening of the mitochondrial permeability transition pore (mPTP), which may induce cell death.^4-7 This process also results in increased oxidative stress, decreased mitochondrial membrane potential (ΔΨm), and decreased cellular adenosine triphosphate (ATP) production due to oxidative phosphorylation uncoupling.⁸ Additionally, impaired mitochondrial biogenesis and mitochondrial deoxyribonucleic acid (mtDNA) damage are other mechanisms that contribute to mitochondrial dysfunction.^9-11

While a number of factors contribute to mitochondrial dysfunction, certain drugs (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), lifestyle factors (i.e., alcohol consumption and cigarette smoking), and environmental pollutants (e.g., bisphenols and heavy metals) have been shown to damage mitochondria via the aforementioned mechanisms. Further, research links these toxins with the aetiology and progression of diseases including age-related macular degeneration (AMD),¹² metabolic syndrome (MetS),¹³ type 2 diabetes mellitus (T2DM),^14-16 and Parkinson’s disease.^17,18

Figure 1. Generation of ROS in Mitochondria¹⁹

NSAIDs Disrupt the mPTP and Induce Liver Injury

NSAIDs provide an exemplary model of how common medications can cause an uncoupling of mitochondrial oxidative phosphorylation, leading to impaired ATP synthesis.²⁰ Some NSAIDs are also known to induce the mPTP and the subsequent development of Reye’s syndrome²¹ and renal toxicity,²² however the pathological role of the mPTP in NSAID-induced liver injury has not been fully clarified.

In an in vivo study investigating the role of the mPTP in the pathogenesis of diclofenac-induced hepatocyte injury in isolated rat livers, incubation of energised mitochondria with succinate in the presence of Ca2+ and diclofenac (12.5 to 100 mmol/L) was shown to open the mPTP. Consequently, mitochondrial swelling, leakage of accumulated Ca2+, decreased ΔΨm, oxidation of nicotinamide adenine dinucleotide phosphate (NADP+), decreased protein thiol content, and decreased cellular ATP production occurred. This study highlighted the importance of the mPTP in the pathogenesis of diclofenac-induced hepatocyte injury.⁸

Impact of Lifestyle-Related Toxins and Oxidative Damage in Liver and Eye Disease

It is also well-established that alcohol alters mitochondrial morphology and function by impairing mitochondrial biogenesis, damaging mtDNA, causing oxidative stress, and inducing hepatocellular apoptosis.^9,10 In vivo, acetaldehyde (20 to 80 μM) has been shown to decrease superoxide dismutase (SOD) activity by 90% and the glutathione (GSH)/oxidised glutathione (GSSG) ratio by 36% in hepatocytes.¹¹ These findings are consistent with other research that has observed similar changes in alcohol-induced mitochondrial liver injury, such as decreased nicotinamide adenine dinucleotide (NAD+)-linked hydrogenases, cytochrome oxidase, and ATP synthase complex activity;²³ and mitochondrial GSH depletion leading to mitochondrial lipid peroxidation.²⁴ Collectively, these studies have established a broader biochemical view of the role of mitochondrial dysfunction in the progression of alcoholic liver disease and identify how sensitisation to repeated oxidative insults occur.^11,23,24

Likewise, cigarette smoke causes oxidative damage, with smokers previously shown to have 24% lower function of complex I mitochondrial activity than non-smokers.²⁵ Further, acrolein, a toxicant in cigarette smoke, has been found to cause oxidative damage and mitochondrial dysfunction in human retinal pigment epithelial (RPE) ARPE19 cells. RPE cell degeneration is often observed in the early stages of AMD. Acute exposure to higher doses of acrolein (≥50 μM for 24 hours) decreased cell viability, ΔΨm, GSH, antioxidant capacity, nuclear factor erythroid 2-related factor 2 (Nrf2) expression, and enzyme activity (mitochondrial complexes I, II, III; SOD, glutathione peroxidase [GPx]); and increased cytosolic Ca2+. Continual exposure to low doses of acrolein (0.1 to 5 μM for 8 or 32 days) similarly induced toxicity, demonstrating a clear link between cigarette smoke, mitochondrial dysfunction, and AMD pathogenesis.¹²

Environmental Toxins Impair Mitochondrial Metabolism in Metabolic and Neurodegenerative Diseases

Environmental chemical toxicants such as bisphenols,²⁶ phthalates,²⁷ dioxins,²⁸ and organophosphate pesticides²⁹ also increase ROS production and reduce cellular ATP, impairing mitochondrial metabolism. An in vivo study evaluating the effects of low-level long-term exposure to bisphenol A (BPA) and BPS (50 μg/kg per day) demonstrated that both compounds alter serum lipid levels and lead to the development of glucose intolerance within 38 weeks. Further findings on the effects of both BPA and BPS highlighted a significant upregulation in the expression of dynamin-related protein 1 (Drp1), essential for mitochondrial fission. BPA also downregulated the expression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis. A reduction in oxidative phosphorylation capacity, uncoupling, and significant increases in fatty acid oxidation by BPA was also seen. Together these results exhibit how daily exposure to plastics alter metabolic homeostasis and mitochondrial energy metabolism, clinically relevant to the underlying drivers of obesity, insulin resistance, MetS, and T2DM.¹⁵

Heavy metals are another environmental factor that impede mitochondrial function. Aluminium,³⁰ mercury,³¹ cadmium,^32,33 lead,³⁴ arsenic,³⁵ and tin³⁶ have been associated with both mitochondrial dysfunction and neurological disorders.³⁷ Evidence of aluminium administration from an in vitro (50 nM Al3+ for 3 min) and in vivo (10 mg Al3+/kg per day for 10 days) study exhibited significant alterations in the capacities of complexes II (in vitro), and complexes III and V (both in vitro and in vivo), effectively demonstrating the impact of aluminium on mitochondrial bioenergetics, the redox environment, and mitochondrial homeostasis. Authors suggested that these changes within the mitochondria may consequently affect the energetic capacity of nigrostriatal dopaminergic neurons, drawing a conclusion on how aluminium acts as an aetiological factor in neurodegenerative disorders such as Parkinson's disease.¹⁸

Toxins Drive Disease at the Mitochondrial Level

Certain medications, alcohol, cigarette smoke, environmental chemical toxicants, and heavy metals have all been shown to disrupt mitochondrial structure and function in different tissues. Imbalances in redox state, overproduction of ROS, and impaired energy production largely constitute the cellular mechanisms of mitochondrial dysfunction seen in NSAID-induced liver injury, alcoholic liver disease, AMD, MetS, T2DM, and Parkinson’s disease. By pinpointing mechanisms through which oxidative stress occurs at the mitochondrial level, practitioners are better equipped to formulate evidence-based treatment plans and counsel patients on diet and lifestyle choices that effectively prevent/manage chronic and age-related diseases.

The information contained within is intended to be used as an educational tool and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice.

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