Dear Editor,

We read with great interest the study by Hinojosa-Gonzalez et al., which underscores the neurocognitive risks associated with androgen deprivation therapy (ADT) for prostate cancer [1]. While ADT’s well-documented systemic toxicities—such as metabolic syndrome and cardiovascular complications—are extensively discussed, we propose that mitochondrial dysfunction serves as the central mechanism driving these effects and further links ADT to neurodegenerative risks.

ADT achieves therapeutic effects by suppressing testosterone, a hormone essential for mitochondrial health. This suppression results in impaired ATP production, increased oxidative stress, and disrupted metabolism, which exacerbate systemic risks [2, 3]. Neurons, due to their high energy demands, are particularly vulnerable, and mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD), suggesting that ADT-induced mitochondrial toxicity may underlie neurocognitive decline in treated patients [4]. Furthermore, the interconnection between mitochondrial dysfunction and oxidative stress not only damages cellular energy production but also triggers a cascade of molecular events that exacerbate the pathological progression of these diseases. The accumulation of reactive oxygen species (ROS) damages lipids, proteins, and DNA, amplifying neuronal vulnerability. This chain reaction highlights the critical role of mitochondria as both a source and target of oxidative stress in ADT-related toxicities.

Further supporting this hypothesis is the role of antidiabetic medications. Insulin, by driving intracellular glucose overload, overwhelms mitochondrial capacity and produces reactive oxygen species (ROS), mimicking the mitochondrial damage observed in ADT [5]. Conversely, glucagon-like peptide-1 receptor agonists (GLP-1) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated protective effects on mitochondria by reducing glucose overload and oxidative stress [5]. These findings not only underscore the centrality of mitochondria in systemic toxicity but also suggest that metabolic interventions may hold promise in addressing ADT-associated neurodegenerative risks. For example, GLP-1 receptor agonists enhance antioxidant pathways and reduce inflammatory signaling, while SGLT2 inhibitors have been shown to restore mitochondrial dynamics and improve cellular bioenergetics. These multifaceted effects illustrate the potential of targeting mitochondrial health as a therapeutic strategy.

As shown in Fig. 1, mitochondrial dysfunction serves as the unifying mechanism connecting ADT, insulin, and neurodegenerative diseases. While ADT and insulin drive mitochondrial overload and oxidative stress, leading to dementia, Alzheimer’s disease, Parkinson’s disease, and depression, GLP-1 and SGLT2i therapies mitigate these risks by preserving mitochondrial function in diabetic patients. This mechanistic link highlights how therapeutic strategies that preserve mitochondrial integrity can potentially reduce both systemic and neurological complications, underscoring the need for comprehensive approaches to managing ADT toxicity.

Fig. 1: Mitochondrial Dysfunction as the Central Mechanism Linking ADT, Insulin, and Neurodegenerative Diseases.
figure 1

This figure illustrates how ADT and insulin drive mitochondrial dysfunction, resulting in neurodegenerative diseases such as dementia, Alzheimer’s disease, Parkinson’s disease, and depression. It also highlights the potential of GLP-1 and SGLT2i therapies to protect mitochondrial health by reducing glucose overload and oxidative stress.

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Recognizing mitochondrial dysfunction as the central mechanism of ADT toxicity represents a paradigm shift in the management of prostate cancer patients. Future research should explore mitochondrial-targeted therapies to mitigate ADT-related risks and improve patient outcomes. Moreover, investigating the precise molecular pathways by which mitochondrial dysfunction contributes to neurodegeneration may open new avenues for intervention. Clinical trials assessing the efficacy of these mitochondrial-targeting agents or exercise in ADT-treated populations could provide critical insights into their translational potential and broader applicability.