Neurodegeneration is an inflammatory response in the central nervous system (CNS). It represents a complex constellation of conditions characterized by the progressive decline in neurons’ structure, function, and viability. This pathological phenomenon is central to various disorders that collectively are known as neurodegenerative diseases (NDs). These conditions—such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and multiple sclerosis (MS)—are unified by their insidious onset and the inexorable deterioration of cognitive, motor, or sensory functions they inflict upon individuals.

These diseases share a gradual onset and a relentless progression of cognitive, motor, or sensory impairments, making them a leading cause of disability worldwide, particularly among older populations. As society ages, the prevalence of NDs is expected to increase, highlighting the critical need for enhanced understanding and development of innovative preventive strategies.

At the cellular level, neurodegeneration is characterised by a series of events including synaptic dysfunction, neuronal loss, and brain atrophy. These processes are driven by the neurons’ inability to sustain necessary biochemical and cellular operations, leading to apoptosis or other forms of cell death (Granatiero et al., 2019; Angelova and Abramov, 2018; Wilson et al., 2023). This results in the breakdown of neural networks and neurotransmission disruption, manifesting in symptoms depending on the affected brain regions. The molecular mechanisms at play, such as mitochondrial dysfunction, oxidative stress, and low-grade inflammation, are pivotal to understanding the pathology of NDs. Mitochondrial dysfunction compromises cellular energy metabolism, contributing to the cell death seen in NDs. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, further damages neurons (Lin and Beal, 2006). Key molecular players in these processes include oxidative stress induction and molecular networks related to neuroinflammation and cellular dysfunction, exacerbating neuronal damage (Sivandzade et al., 2019).

The environmental and lifestyle factors, including diet, physical activity, and exposure to toxins, further modulate the risk and progression of neurodegenerative diseases. Here, the role of diet emerges as both a potential risk factor and a protective ally against neurodegeneration (Solfrizzi et al., 2017; Zhang et al., 2021; Bianchi et al., 2021; Yang et al., 2021; Godos et al., 2024). Nutritional patterns rich in polyphenols and healthy fats can mitigate the risk of neurodegenerative diseases by influencing the molecular mechanisms of neurodegeneration. Diets that reduce oxidative stress, dampen low-grade inflammation, and improve mitochondrial function can significantly impact the progression of these diseases. Additionally, consistent consumption of fruits like berries and cherries, which are high in polyphenols, may contribute to maintaining cognitive health (Wang et al., 2023). Investigating phytocomplexes used in folk medicine could lead to the discovery of compounds with diverse preventive benefits across various diseases, including cancer (Micucci et al., 2024), cardiovascular issues (Micucci et al., 2020), and neurological disorders (Lapi et al., 2020).

The exploration of phytocomplexes derived from plants such as Acacia catechu (Chiaino et al., 2021), Castanea sativa (Brizi et al., 2016), Olea europea (Chiaino et al., 2020), and phytochemicals like flavonoids and curcumin have unveiled their potential to modulate critical molecular pathways involved in neurodegeneration. These substances can inhibit the activation of NF-κB, thereby reducing the production of pro-inflammatory cytokines such as IL-1 and IL-6. They also promote the activation of Nrf2, enhancing the cellular antioxidant response and protecting against oxidative damage (Abrahams et al., 2019; Calis et al., 2020; Farzaei et al., 2019). Indeed, generally, flavonoids lead to a reduction in ROS, regardless of their source (endogenous: mitochondria, peroxisomes, xanthine oxidase, Fenton reaction, NADPH oxidase, lipoxygenases, cytochrome P450 or exogenous: visible, UV and ionising radiation, chemotherapeutics) (Kicinska and Jarmuszkiewicz, 2020). Additionally, compounds naturally occurring in the human body, such as melatonin and Coenzyme Q10 (CoQ10), have also been studied and extracted, leading to the development of novel agents to mitigate oxidative stress and support mitochondrial function in neurodegenerative conditions (Areti et al., 2017; Bagheri et al., 2023).

Amidst these complex interactions, CoQ10 and its derivatives stand out for their dual role in mitochondrial function and antioxidant defence. Coenzyme q10 provides a promising avenue for neurodegerative disorders, acting on oxidative phosphorylation, which occurs in the mitochondria via the electron transport chain, the primary process responsible for ATP production (Kang et al., 2020). However, challenges in bioavailability and optimal dosing underscore the need for further research to harness CoQ10’s full potential in combating NDs.

This study introduces a pioneering in vitro comparison of a novel CoQ10 analog with CoQ10, focusing on their neuroprotective effects and underlying mechanisms in HT22 neuronal cells. Our investigation delves into mitochondrial ROS modulation, regulation of genes implicated in mitochondrial biogenesis and function (PGC-1ɑ, TFAM, MT-ND1, MT-COI, MT-COX5B), and OXPHOS subunit protein expression, aiming to illuminate the novel analog’s superior efficacy and mechanism profiles. Finally, SEM and TEM analyses suggest neuroprotective effects evidence by preserved mitochondrial integrity, reduced apoptotic cells, autophagic vacuoles, and cellular morphology in the treatment group compared to controls. This work represents a significant stride in overcoming CoQ10’s dosing challenges, potentially setting a new benchmark in neuroprotective strategies.

The findings from this study highlight the significant protective effects of Q-Der on HT22 neuronal cells, particularly under conditions of oxidative stress induced by rotenone. This condition offers a targeted model for studying mitochondrial dysfunction, as it selectively inhibits Complex I of the electron transport chain, disrupting ATP synthesis and causing localized ROS generation (Menke et al., 2003; Moon et al., 2005). This inhibition leads to mitochondrial membrane depolarization, increased expression of mitochondrial fission markers and activation of caspase-3-dependent apoptotic pathways. These effects are highly relevant to neurodegenerative diseases like Parkinson’s disease, where mitochondrial dysfunction and selective dopaminergic neuronal death are central features (Moon et al., 2005; Li et al., 2017). Several stressors act on neurons through the affection of the same pathways targeted by rotenone. For example, H₂O₂ induces oxidative stress generating ROS across multiple cellular compartments, leading to generalized oxidative damage that is not specific to mitochondria. Despite this distinction, both rotenone and H₂O₂ share some key effects, including ROS generation, mTOR pathway suppression, apoptotic activation involving caspase-3 cleavage and PARP fragmentation. These shared mechanisms provide complementary insights into oxidative stress and neuroprotection, with rotenone being a specific tool for the study of mitochondria-dependent neurodegenerative pathologies (Panee et al., 2007; Zhou et al., 2015; Giraldo-Berrio et al., 2024; Roy et al., 2023; Millichap et al., 2024).

Our study focuses on rotenone-induced oxidative stress due to its mitochondria-specific effects. Our results add to a growing body of evidence that underscores the importance of targeting mitochondrial dysfunction in neurodegenerative diseases such as Parkinson’s and Alzheimer’s, where oxidative stress plays a pivotal role. Q-Der demonstrated substantial efficacy in reducing cell death, restoring mitochondrial superoxide levels, and modulating key gene expressions involved in mitochondrial biogenesis and respiration. While the protective effects of Q10 have been well-documented in similar models (Bhagavan and Chopra, 2006), the current data suggest that Q-Der may offer superior benefits, particularly in maintaining mitochondrial homeostasis under stress conditions.

Chemically, Q-Der differs from Coenzyme Q10 in that it carries two acetyl groups on its quinone ring, increasing its lipophilicity and potentially enhancing its stability against oxidation. While CoQ10 functions through rapid cycling between oxidized and reduced forms to neutralize reactive oxygen species, the addition of acetate groups in Q-Der is theorized to confer a protective effect on the molecule itself, reducing its reactivity to oxidative agents. This structural modification may support a prolonged antioxidant presence within the mitochondrial membrane, thus maintaining cellular protection over extended periods of oxidative stress. These properties underscore Q-Der’s potential as a neuroprotective agent, particularly in environments where mitochondrial stability and sustained antioxidant effects are essential.

A key aspect of this study is the ability of Q-Der to preserve mitochondrial function and ROS levels. Compared to Q10, Q-Der consistently showed a trend toward better protection against oxidative stress markers such as mitochondrial superoxide, although this trend did not reach statistical significance. This mirrors findings in other studies where derivatives of Q10, such as MitoQ and Ubidecarenone, have been shown to exhibit enhanced mitochondrial targeting and antioxidant properties compared to the parent compound (Smith and Murphy, 2010). MitoQ, a mitochondria-targeted form of CoQ10, has demonstrated strong efficacy in reducing mitochondrial ROS and improving bioenergetics by selectively accumulating in the mitochondrial membrane, facilitating more effective protection against oxidative damage (Cochemé et al., 2007). Although MitoQ and Q-Der share similarities in their mechanisms of action—both aim to enhance mitochondrial function by modulating ROS levels—the differences in their molecular structures likely contribute to their varying degrees of efficacy. For instance, MitoQ’s triphenylphosphonium cation facilitates its direct accumulation in the mitochondria, while Q-Der may rely more on its metabolic conversion within cells.

The qRT-PCR analysis further underscores the potential of Q-Der, particularly in its ability to upregulate key genes involved in mitochondrial biogenesis, such as PGC-1α and TFAM. This is consistent with literature indicating that compounds enhancing PGC-1α activity could promote mitochondrial biogenesis and repair, thereby offering neuroprotection (Wenz, 2009). The upregulation of PGC-1α and partial rescue of TFAM under rotenone-induced oxidative stress suggest that Q-Der helps restore mitochondrial integrity and function, which is crucial for maintaining ATP production and preventing cellular apoptosis. Comparatively, studies on other Q10 derivatives like Q10-hydroxydecyl benzoate (IDE) have shown similar mitochondrial-protective effects, particularly in preventing the loss of complex I and complex III activity, further highlighting the importance of preserving mitochondrial bioenergetics in disease models (Villalaín, 2004). However, Q-Der’s ability to modulate both mitochondrial biogenesis and complex V expression distinguishes it as a promising candidate for further exploration.

The Western blot analysis revealed that while there were no significant changes in the expression of CI-NDUFB8, CII-SDHB, or CIII-UQCRC2 across the treatment groups, Q-Der significantly increased CV-ATP5A (complex V) expression in rotenone-treated cells. This result is particularly noteworthy, as complex V is essential for ATP synthesis, and its dysfunction is a critical contributor to energy deficits observed in neurodegenerative diseases (Nicholls and Budd, 2000). The statistically significant recovery of CV-ATP5A in Q-Der-treated cells indicates that this novel compound effectively preserves mitochondrial ATP production capacity under oxidative stress conditions. This protective effect on ATP synthase has also been observed in studies using idebenone, a synthetic analog of CoQ10, which has shown promise in clinical trials for conditions such as Friedreich’s ataxia and Leber’s hereditary optic neuropathy (Schiff and Rustin, 2016; Lyseng-Williamson, 2016). While idebenone primarily targets complex I deficiency, the broader effect of Q-Der on many mitochondrial parameters suggests a more comprehensive mitochondrial support mechanism.

An interesting finding in our study is that, despite QDer improving numerous parameters of mitochondrial function, it does not appear to increase the levels of UQCRC2, a key component of Complex III of the electron transport chain. This result may seem to contrast with well-established CoQ10-mediated regulation of other mitochondrial markers (Yousef et al., 2019). One possible explanation is that QDer exerts its effects primarily on Complex I or V, leaving Complex III relatively unaffected. Additionally, UQCRC2 levels might already be saturated under basal conditions, leaving little room for further regulation. Studies on PARL-deficient models demonstrate selective defects in Complex III mediated by TTC19 instability without impacting other complexes of the ETC (Spinazzi et al., 2019).

Furthermore, the partial increase in Complex III activity observed in idebenone-treated models suggests that increased protein expression does not always correlate with functional recovery (Llewellyn et al., 2015). Similarly, the unchanged GSSG:GSH ratio in the cerebellum suggests that certain oxidative stress markers may resist modulation even under treatment.

Morphologically, the structural preservation observed through SEM and TEM further supports the molecular data. Even after rotenone exposure, cells pre-treated with Q-Der exhibited well-preserved cellular morphology and mitochondrial structure. This contrasts with the significant cytoskeletal and mitochondrial damage seen in rotenone-treated cells, aligning with the concept that maintaining mitochondrial integrity is crucial for cellular survival under oxidative stress. Studies on other derivatives, such as SkQ1 (a plastoquinone derivative), have also demonstrated the importance of targeting mitochondrial health to prevent structural damage in neurons, supporting the idea that mitochondrial-targeted therapies can significantly affect disease progression (Fedorov et al., 2022; Sacks et al., 2021). However, while SkQ1 is known for its anti-apoptotic properties, Q-Der offers a broader protective mechanism by reducing oxidative stress and enhancing mitochondrial gene expression, further solidifying its role as a potential neuroprotective agent.

In conclusion, the results of this study place Q-Der in a promising position as a neuroprotective agent aimed at preserving mitochondrial function, particularly in NDs. While other derivatives of Q10, such as MitoQ, idebenone, and SkQ1, have shown efficacy in specific mitochondrial pathways, Q-Der appears to provide a multifaceted approach, combining antioxidant effects, mitochondrial biogenesis and enhanced ATP production. The statistical significance observed in the restoration of CV-ATP5A expression and the trends toward improvement in mitochondrial superoxide levels and gene expression positions Q-Der as a strong candidate for further in vivo studies and eventual clinical translation. Future research should aim to explore the exact molecular pathways through which Q-Der exerts its effects and to compare its efficacy in vivo against other Q10 derivatives in models of neurodegeneration. Additionally, a deeper understanding of the pharmacokinetics and bioavailability of Q-Der relative to other mitochondrial-targeted therapies will be crucial in determining its therapeutic potential.

The present study provides compelling evidence of Q-Der’s neuroprotective efficacy in HT22 cells, highlighting its ability to attenuate rotenone-induced oxidative stress and preserve mitochondrial function. Q-Der’s effects were evident through significant reductions in mitochondrial superoxide production, enhanced expression of mitochondrial biogenesis genes (PGC-1α and TFAM), and the upregulation of complex V ATP synthase, contributing to sustained ATP synthesis under stress conditions. These findings support Q-Der as a possible candidate for further investigation in neurodegenerative disease models, particularly those characterized by mitochondrial dysfunction and oxidative stress.

While this study establishes Q-Der’s protective effects in vitro, its translational potential requires further examination. The exclusive use of HT22 cells limits applicability across broader neuronal models, and in vivo studies are essential to confirm bioavailability and metabolic stability. Future research should expand to diverse cellular models and focus on Q-Der’s pharmacokinetics to substantiate its therapeutic promise.