Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.
Psychosis is a characterizing feature of many mental disorders that dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and what is not. Both genetic and environmental factors, such as stressful events or drugs use, play a pivotal role in the development of symptomatology and therefore changes in the epigenome may be of relevance in modeling a psychotic phenotype.According to the well-documented dysregulation of endocannabinoid and dopaminergic system genes in schizophrenia, we investigated DNA methylation cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes in saliva samples from psychotic subjects using pyrosequencing.The epigenetic mark was significantly higher and directly correlated for both genes in psychotic subjects compared to healthy controls. We also showed that these DNA methylation levels were lower in psychotic subjects reporting current delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, resembling those of controls at least for the DRD2 gene. Overall, our data confirm the key role of CNR1 and DRD2 gene regulation in psychosis and suggest DNA methylation levels at specific CpG sites as potential biomarkers, but just in those psychotic subjects not consuming THC.
Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ9-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.
Psychosis is a characterizing trait of many mental disorders which dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and not real. Both genetic and environmental factors, such as stressful events or drug of abuse consumption, play a pivotal role in the development of the symptomatology and thus alterations in the epigenome could be of relevance in modelling a psychotic phenotype.According to the well documented dysregulation of the endocannabinoid and dopaminergic system genes in schizophrenia, we here evaluated cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes DNA methylation in saliva samples of psychotic subjects by pyrosequencing.We observed, in patients when compared to healthy controls, a significant increase of both CNR1 and DRD2 DNA methylation levels, and these resulted also significantly correlated. We also showed that in subjects reporting delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, DNA methylation levels for DRD2 resulted to be reduced. Interestingly, in both genes, we highlighted an inverse correlation between DNA methylation levels and clinical symptoms. Overall, our data confirm the key role of CNR1 and DRD2 genes regulation in psychosis and their potential relevance as biomarkers associated to this pathological condition.
