Over the years, it has become clear that neuropsychiatric disorders share several specific commonalities, most notably a proinflammatory profile and increased levels of oxidative stress that are also shared with other disorders (Esch et al., 2002; Esch and Stefano, 2002). While the proinflammatory events taking place in specific microenvironments may be contributing to detection and repair processes, these phenomena may also be contributing to several distinct clinical conditions and disorders. The pro-inflammatory state may be a reflection of immune and/or neural mediators that play critical roles in normal intrinsic events such as maintenance or surveillance, but that were recruited at an abnormal time or to an abnormal extent. In this case, these dysregulated proinflammatory events could promote the accumulation of degenerating neurons, activated immune cells (e.g., microglia) (Stefano et al., 1994), and metabolic residues (e.g., protein aggregates, aberrant glycation, and lipid peroxidation). Similarly, proinflammatory states initiated in response to ordinary conditions may not undergo regulated termination, thereby leading to a chronic state of activation and progressive deterioration (Stefano and Scharrer, 1994).

Several beneficial functions have been attributed to mitochondrial-derived oxidative stress, i.e., ROS, including its antimicrobial properties and role in maintaining vascular tone, among others (Wang and Zhao, 2009). Likewise, under homeostatic conditions, nitric oxide (NO) radicals regulate cardiovascular, neural, and immune functions (Atkins and Sweatt, 1999; Hu et al., 2006; Lu et al., 2007). However, when aberrantly expressed ROS can have deleterious effects, including the capacity to damage proteins, denature lipids and membranes, and alter nucleic acid structure (Mehta et al., 2012). Because the brain is a specialized and relatively closed compartment, it is particularly susceptible to ROS-mediated damage. The brain is also very sensitive to the impact of ROS due to its comparatively large need for oxygen; a full 20% of the total body consumption of oxygen is utilized by the brain.

Based on results from our earlier work, we hypothesized that hypoxia serves as a physiological sensory mechanism that alerts mitochondria to the need to re-establish a healthy metabolic state (Stefano and Kream, 2015a). ROS generated in response to hypoxia can initiate damage via its capacity to destroy several critical biochemicals (e.g., DNA) and thus induce pathology at the organismic level. In addition to cellular dysfunction, ROS may have a signaling function as it can alert the cell to the onset of hypoxia and facilitate the appropriate response. Based on this scenario, hypoxia-mediated alterations to energy metabolism and production of ROS will decelerate mitochondrial function and provide the time needed to adjust and return to homeostasis. Hence, hypoxia may herald a recuperative period; this period may be prolonged by the generation of ROS. However, an overly-traumatic initial assault may overcome these corrective processes. Life overall is an open-ended process and not a loop; thus protective processes can fail even in response to what could be helpful processes. Thus, this short-lived positive response to ROS may be masked depending on the specific insult and the nature of the resulting pathophysiology.

Furthermore, brain tissue contains relatively high concentrations of polyunsaturated (and thus peroxide-sensitive) fatty acids as well as iron, which may also contribute to the pro-oxidative environment. These factors may contribute to the negative sequelae associated with hemorrhagic stroke. Dopamine and GLU oxidation can occur under ischemic conditions and thus exacerbate a proinflammatory state (Badjatia et al., 2012; Mehta et al., 2012; Chen et al., 2013). Lipid peroxidation also yields toxic compounds (e.g., aldehydes) (McCracken et al., 2000). Other dysfunctional modifications include enhanced endonuclease-mediated DNA fragmentation (Cui et al., 2000).

Further cascading pathological pathways resulting from ischemia-associated excitotoxicity and other neurodegenerative insults are triggered by enhanced mitochondrial uptake of calcium by mitochondria and the ensuing synthesis of ROS (Opii et al., 2007; Panov et al., 2007; Hansson et al., 2008; Lemasters et al., 2009). This may occur via inhibition of the proton gradient via interference with the mitochondrial pore. Because the mitochondrial matrix is negatively charged in this setting, the resulting K⁺ inflow can result in osmotic swelling (Rasola et al., 2010). This cascading series of events will also result in the failure of oxidative phosphorylation and thus result in diminished ATP synthesis. Similar results may emerge in response to virus-induced modulation of cellular Ca²⁺ homeostasis, transcription factor activity (e.g., by human immunodeficiency virus |HIV-1| p300 protein), plasma membrane pumps and channels (e.g., in response to the HIV-1 tat and gp120 proteins), and mitochondrial membrane permeability and potential; these perturbations may result in long-term metabolic alterations (Zhou et al., 2009) (Figure 1).

Hence, numerous studies have described the prevalence of oxidative stress and mitochondrial abnormalities in patients diagnosed with one of several characterized neuropsychiatric disorders (Halliwell, 2006; Arranz and de Leon, 2007; Bouayed et al., 2007; Masood et al., 2008; Tsaluchidu et al., 2008; Bouayed et al., 2009; Marazziti et al., 2012; Tobe, 2013). Specific evidence supporting the role of oxidative stress has been reported in cases of schizophrenia (SCZ), anxiety-related disorders, and mood disorders (Ng et al., 2008; Hovatta et al., 2010). For example, mutations in PTEN-induced kinase 1 (PINK1) may be coupled to oxidative stress and mitochondrial fragmentation (Dagda et al., 2009). In this regard, cGMP-protein kinase G (PKG) signaling pathways (Boess et al., 2004; Werner et al., 2004; Masood et al., 2008), NOX2 processes (Wang et al., 2013) and epigenetic mechanisms (Kano et al., 2013) are factors at play in the pathogenesis of SCZ-related psychiatric disorders. Hence, glutathione deficiency and oxidative stress have been identified as contributing factors to both SCZ and bipolar disorders (BPD) (Kunz et al., 2008; Gigante et al., 2011; Kulak et al., 2013; Wass and Andreazza, 2013) as well as autistic behavior (Rose et al., 2012; Gu et al., 2013). Lipid peroxidation has also been associated with BPD and, somewhat more loosely, with the pathogenesis of SCZ (Versace et al., 2014). Interestingly, oxidative damage associated with NO has also been implicated in the pathogenesis of SCZ and BPD (Wass et al., 2006; Palsson et al., 2009) (Levkovitz et al., 2010). Further implicating mitochondrial dysfunctionality is the finding that electron transport subunits occur at lower levels in these disorders, increasing the presence of ROS (Scola et al., 2013). In both BPD and SCZ higher levels of dopamine are found as well as GLU, chemical messengers which also enhance oxidative stress (Coyle, 2013). Abnormalities associated with the electron transport chain (ETC) system and the mitochondrial complex dysfunctions are also proposed to be involved in autism spectrum disorders (ASD) (Rossignol and Frye, 2012; Gu et al., 2013). Aberrations in pyruvate dehydrogenase activity and copy number variations in mtDNA have been detected in association with autism (Gu et al., 2013). Thus, it appears autism is connected to neuronal dysfunctions associated with metabolic abnormalities in oxidative stress and mitochondrial dysfunction (Ming et al., 2008; Rossignol and Frye, 2012; Frye et al., 2013).

The results of a study published by Bajpai et al. (2014) highlighted the close relationship between ROS, mitochondria-energy perturbation, and neuropsychiatric symptoms. The study was conducted on 60 patients diagnosed with unipolar depression and a matching control group of 40 healthy individuals. An analysis of blood samples revealed that the individuals diagnosed with unipolar depression exhibited significantly elevated levels of the lipid peroxidation marker, malondialdehyde (MDA). Production of MDA increases in response to elevated levels of free radicals. Interestingly, serum levels of several critical antioxidants, including nitrite, ascorbic acid, and superoxide dismutase (SOD) were all significantly lower than the levels detected in the control group. Collectively, these results suggested that the oxidant and antioxidant systems were not in balance in patients with unipolar depression. This apparent imbalance may be maintained and exacerbated by psychological stress and associated neuronal inflammation (Figure 2). Similar effects were reported by Lu et al. (2022). In this publication, the authors performed a bidirectional Mendelian randomization analysis of potential causal associations between 11 biomarkers of oxidative stress injury that were evaluated in seven defined psychiatric disorders. The results of this analysis revealed an association of decreased serum levels of ascorbate and bilirubin in individuals diagnosed with ADHD and major depressive disorder (MDD); the authors also noted a nominal association between altered uric acid levels and BPD, ADHD, MDD, SCZ, and anorexia nervosa. Collectively, these results suggest that dysregulated oxidation-antioxidation and a pro-inflammatory environment are linked to the pathogenesis of several common psychiatric disorders. Similarly, results reported by Paternoster et al. (2022) also suggested a link between genetic variation, mitochondrial dysfunction, and psychopathology based on an in silico analysis of the impact of disruption of the gene encoding bromodomain containing 1 (BRD1) on mitochondrial function. Interestingly, associations between genetic variation in BRD1 and mental illness have been demonstrated in several genetic studies. Collectively, these findings indicate that modulation of BRD1, which is a known transcriptional regulator of nuclear-encoded mitochondrial proteins, will lead to alterations in mitochondrial physiology, metabolism, and bioenergetics. BRD1-deficiency-associated neuronal changes may have a critical impact on this mechanism and may lead to one or more of the psychopathological manifestations. Finally, results of a study conducted by Baghel and Thakur (2019) revealed that voltage-dependent anion channel 1 (Vdac1), a mitochondrial membrane porin that mediates the transport of energy-associated ions and metabolites (i.e., Ca²⁺, ATP/ADP) has an impact on recognition memory when differentially expressed in the hippocampus. Among their findings, the downregulation of hippocampal Vdac1 in scopolamine-induced amnesic mice as well as its silencing in untreated mice were both associated with mitochondrial disruption, decreased total ATP levels, increased ROS, decreased antioxidant activity, and neuronal degeneration. These findings provide insight into new pathways for brain energy perturbation that have a critical effect on memory, cognition, and potentially mental health.

Hence, the most effective interventions may be those that have a profound impact on mechanisms that modulate acute and chronic inflammation, including those that focus on increasing the level of antioxidants over an extended period (Filiou and Sandi, 2019; Maurya et al., 2022b). Other interventions might target the mitochondria to limit or reduce the impact of a prolonged excited state. Collectively, these findings illustrate that increases in the brain levels of both oxidative and nitrosative stress (reactive nitrogen species [RNS]) combined with a decrease in the antioxidant capacity may be key factors contributing to the etiology of neuropsychiatric disorders and states of consciousness.

Results from a series of recent studies strongly suggested that virus-mediated perturbations of mitochondrial function that serve to alter cognition may represent an evolutionarily-conserved response to promote viral survival (Singh et al., 2020; Wang et al., 2020; Stefano et al., 2021; Stefano and Kream, 2022a; Stefano and Kream, 2022b; Buttiker et al., 2022). This targeting hypothesis is based largely on observations focused on the long-term evolutionary co-existence of viruses and prokaryotes, specifically noting that prokaryotic cells have served as an ancient primary target of virus-mediated interactions (e.g., infection with bacteriophages). Given that mitochondria were derived from prokaryotic organisms, this organelle may continue to serve as a prime focus for virus infection. Once the mitochondria have been infected, the virus may then have direct access to the nuclear genome. The intracellular transport of mitochondrial (mt)DNA as nuclear-mitochondrial segments (NUMTs) is an evolutionarily ancient phenomenon (Wei et al., 2022). Of interest, Wei et al. (2022) analyzed whole-genome sequences from 66,083 individuals and found that this transfer process is ongoing and that 90% of these NUMTs underwent transfer comparatively recently in evolutionary terms, i.e., after humans diverged from apes.

Hence, the evolutionary competition between ancestral prokaryotes and viruses based on natural selection and conformational matching of chemical messengers may have been carried forward by mitochondria into eukaryotic cells, emerging most notably in tissues that involve high energy and oxygen demands, such as the brain. As a result, the behavior and function of target tissues (e.g., neuronal cells) may have been subject to alterations that facilitated evasion of the host immune response to material identified as “non-self.” Changes of this nature may have also permitted these cells to become more susceptible to virus infection, replication, and propagation (Stefano et al., 2021). The earliest historical data from human pandemics provided us with a set of intriguing observations, particularly those that identified cognition as a central target even in cases in which the actual causal agent remained unknown. These observations support our view that the brain, most notably the human brain, was and remains an important target because its immune-privileged status permits pathogens to evade the host immunosurveillance (Buttiker et al., 2021b; Stefano, 2021; Buttiker et al., 2022; Stefano, 2021). In our earlier work, we proposed several different neuroinvasive strategies by which viruses (e.g., human immunodeficiency virus 1 [HIV-1], severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], herpes simplex virus 1 [HSV-1], and Ebola virus, among others) may cross the blood-brain-barrier (BBB). By doing so, these pathogens can exploit the immune privilege of the central nervous system (CNS) to harbor viral genomes. This will permit them to replicate without detection and elicit persistent CNS infection, leading to neuronal dysfunction (Stefano et al., 2022a; Buttiker et al., 2022). Thus, we hypothesize that these viruses may rely on complex signaling pathways and ancient mechanisms of information exchange to hijack the cellular reproductive machinery and alter mitochondrial function. These metabolic disruptions may ultimately lead to many common neuropsychiatric sequelae (Buttiker et al., 2021b; Stefano et al., 2021).

This ancient record of virus-bacteria interactions and its role in promoting altered cognition has been highlighted further by recent findings focused on the increased expression of ancient human endogenous retrovirus type W (HERV-W) envelope (Env) proteins in blood samples from patients diagnosed with psychosis and other neurodevelopmental psychiatric disorders (Balestrieri et al., 2019). Of note, 8% of the sequences found in the human genome originated from HERV infections that occurred millions of years ago (Angrand et al., 2021; Tamouza et al., 2021; Burn et al., 2022). Several groups have reported the increased expression of HERV in SCZ and BPD as well as in various cancers (Diaz-Carballo et al., 2017; Angrand et al., 2021; Tamouza et al., 2021; Burn et al., 2022). In a recent study, Tamouza et al. (2021) detected HERV-W Env proteins in serum samples from subsets of patients with SCZ (−41%) and BPD (−28%), while 96% of the control samples remained negative. These results suggest that the detection of immunoreactive HERV-W Env proteins may be of diagnostic value. Consistent with these findings, Johansson et al. (2020) demonstrated that HERV-W-associated neuropsychiatric symptoms may involve Toll-like receptor 4 (TLR-4) mediated activation of glial cells; the proinflammatory cytokines released in response to this interaction may have an impact on N-methyl-D-aspartate (NMDA)-linked synaptic organization in hippocampal networks and thus synaptic GLU activity.

Activation of immune cells (e.g., microglia, astroglia, and macrophages) and release of inflammatory cytokines can increase synaptic GLU, ROS, and RNS, leading to oxidative stress and a spillover of GLU from synapses into the extrasynaptic space (Haroon et al., 2017). This response may have a negative impact on the number and activity of excitatory amino-acid transporters (EAATs) and lead to further decreases in the astrocyte-mediated clearance of the accumulated GLU. Collectively, these responses will increase the concentration of extrasynaptic GLU, leading to neuronal hyperactivity and excitotoxicity. This effect can be explained at least in part by acute overactivation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA ionotropic receptors. Prolonged stimulation of presynaptic metabotropic glutamate receptors (e.g., mGluR2/3) and overstimulation of intrasynaptic AMPA receptors may lead to desensitization and loss (Haroon et al., 2017). Hence, over time, acute neuronal overactivity may result in diminished intrasynaptic glutaminergic activity; this may have a direct impact on the function of CNS circuits due to neuronal atrophy and loss. Collectively, these findings suggest that acute and chronic mitochondrial dysfunction, oxidative stress, and aberrant glial function may have significant effects on neuronal communication by altering the synthesis, regulation, and thus the overall balance of excitatory and inhibitory neurotransmitters (Hertz, 2013).

Complementing these studies, Angrand et al. (2021) reported low copy numbers of circulating mtDNA in patients diagnosed with BPD patients at levels that negatively correlated with scales of mood and psychotic disturbance. Diaz-Carballo et al. (2017) reported that cytotoxic stress resulted in the transfer of mitochondria-associated HERV proteins into adjacent cancer cells via both tunneling tubes also direct cellular uptake with a considerable translocation (i.e., accumulation) of mitochondria around the nucleus. Collectively, these results highlight the multidimensional nature of genetic material and its participation in multiple interactions regardless of its source or origin.

In summary, we hypothesize that, in addition to their expression in the nuclear genome, both viral DNA and mtDNA retain the capacity to communicate with one another and thereby alter cognitive processes (Stefano et al., 2021; Stefano and Kream, 2022a; Stefano et al., 2022b; Stefano and Kream, 2022b; Stefano et al., 2022d). The collective results of numerous published studies suggest that ancient viruses not only remain within the genome, but they can also be activated and expressed in current-day tissues and organisms. However, given their ancient status and their long history of targeting prokaryotic organisms (both bacteria and mitochondria), the viruses emerging today may be poorly-adapted and thus unable to carry out effective interactions with newly-evolved structures associated with human cognitive processes. Hence, the expression of these viruses may result in perturbed cognition. We hypothesize that this response may favor pathogen survival by blunting and/or hijacking one or more of these newly-evolved protective responses, notably those associated with the immediate and ongoing requirements for oxygen-derived energy (i.e., oxidative phosphorylation). Taken together, the dynamic co-evolutionary process that has provided both viruses and bacteria with the opportunity to undergo change/mutation remains under the influence of natural selection. An improved understanding of this relationship will provide us with the means to develop novel therapies that address potentially-related psychiatric disorders and pathologies, for example, bacterial “Trojan horses” that carry chemical intervention agents.

From a cognitive perspective, mitochondrial dysfunction and oxidative stress may cause perceptual perturbations and neuropsychiatric symptoms via brain energy modulation of high-energy demanding neuronal structures (Khacho et al., 2017; Wei et al., 2019; Daniels et al., 2020; Esch et al., 2020; Buttiker et al., 2021b; Picard and Sandi, 2021; Song et al., 2021). This perturbation may be due to intrinsic, for example, epigenetically altered expression of ancient retroviral proteins or various exteroceptive-induced (e.g., immunological) responses and involve the recruitment, translocation, and accumulation of healthy and/or mutated mitochondria (e.g., additional oxygen supply) from surrounding tissues (Wang and Gerdes, 2015; Diaz-Carballo et al., 2017) together with the discussed metabolic dysregulation of mitochondria (i.e., maladaptive molecular interaction) at the site of inflammation (Figure 1). The subsequent shift in brain energy allocation and aberrant local metabolite generation and accumulation (e.g., GLU, ROS, etc.) may cause primary disruption (e.g., hyperactivation, atrophy) of the affected structures (Haroon et al., 2017) and possibly secondary disruption (i.e., energy/oxygen deduction) of other for cognition important high-oxygen demanding systems, such as, for example, the default mode network (DFM). The DFM is a large-scale integrative network responsible for controlling the integration of exteroceptive stimuli and deactivation of external sensory information during resting states, and which interruption is associated with disturbed self-perception and many psychiatric disorders, such as depression, anxiety, and schizophrenia (Xu et al., 2016; Qiao et al., 2017). Hence, acute neuronal inflammation of structures, such as components of the limbic system (e.g., hippocampus), that are essentially involved in memory consolidation and emotional processing can be a powerful promoter of erroneous signal integration into large-scale integrative networks, such as the DFM, creating an energy landscape for maladaptive learning and information processing (Weeber et al., 2002; Angulo et al., 2004; De Chiara et al., 2019).

In a predictive coding model, such disruptions decrease the predictable reliance on affected structures fostering maladaptive forwarding and integration of information into higher-order processing regions of the brain (Buttiker et al., 2021a). If we accept higher function and integrative control networks, such as the DFM, to display naturally high-weighted predictive reliability, their chronic disturbance may not merely lead to temporary disruption of perception, but a persistent modulation of internal concepts and neuropsychiatric sequelae following chronic oxidative stress and mitochondrial dysfunction (Raymond et al., 2017; Buttiker et al., 2021b).

We hypothesize that these mechanisms and ancient evolutionary factors emerged at the same time as cognition and the availability of high-energy producing and high-energy requiring organ systems such as, for example, the CNS. Hence, deeply-embedded primal emotions and associated neuropsychiatric behaviors, including fear-anxiety, sadness-depression, and anger-aggression, among others, may represent a pathway that supports both host-restorative processes and also pathogen replication. Ancient genomic (HERV) and mitochondria sequences become naturally adapted to their microenvironments and thus will ultimately become actively involved in the development of responses to exteroceptive and interoceptive changes and the need to communicate factors associated with different neuronal states. For example, following distressing external/internal events, these sequences may be central to the development of immune activation. The active involvement of both bacteria and viruses in processes associated with brain energy transformation and the generation of neurotransmitters may result in their capacity to “hijack” cellular metabolism. It may also permit bacteria and viruses to use one or more associated predicted constructs (e.g., host behaviors and emotions) to their own advantage. For example, they may develop the capacity to mirror the neuronal conditions associated with depression by using the associated lower energy requirements to mask their own replication. This may deceive the host, who will perceive feelings of depression rather than signs or symptoms of an acute infection. The same situation might be used to explain generalized anxiety and/or psychosis; in this case, hyperactive neuronal structures associated with anxiety symptoms may be used to mask viral activity.

Short-term perturbations may in some cases represent a survival strategy that benefits both the pathogen and the host (Figure 3). As previously discussed, a shift in the allocation of brain energy and generation of metabolites and the resulting alterations in the neuronal microenvironment can induce a temporary change in host perception. This metabolic perturbation may promote pathogen proliferation via a symbiotic-parasitic diversion of non-essential neuronal energy from the host while at the same time promoting host protection via behavioral adjustments based on external and/or internal circumstances. Examples of this symbiotic-parasitic collaboration might include episodes of depression (e.g., after the loss of a loved one or recovery from a disease or infection, among others), in which physical and mental energy are reduced in the effort to stimulate host recovery; in these cases, the excess energy may be used instead to support pathogen proliferation. Thus, the induction of altered states of consciousness, including confusion, disorientation, and even in some cases anxiety or depression, may serve as positive restorative actions that protect the host. At the same time, some pathogens (e.g., SARS-CoV-2 and HIV-1, among others) may have evolved so that they can induce and/or utilize these cognitive alterations via natural selection processes that are sustained and still ongoing as of this day (Stefano et al., 2021; Maurya et al., 2022a; Buttiker et al., 2022; Stefano et al., 2022c).