Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder

Abstract

Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

“…For validation of human DLPFC findings, we used a small case-control dataset (15 controls, 15 SCZ cases) with associated toxicology derived from brain tissue (cerebellum) as previously described [43]. Raw gene expression data was processed using adapter trimming via cutadapt and pseudoalignment to the human transcriptome (GENCODE v32) via Salmon [44].…”

Şizofreni hastalarında CYB mtDNA mutasyonları ve PI3K/AKT/mTOR sinyal yolağındaki genlerin ekspresyon durumu

“…mtDNA'daki genetik değişikliklere bağlı olarak bozulmuş mitokondriyal fonksiyonun, zihinsel bozukluklar da dahil olmak üzere farklı anormal nörolojik durumlara katkıda bulunabileceği varsayılmıştır 6 . Mitokondriyal disfonksiyon, sinaptik nörotransmisyonu sinerjistik olarak etkileyebilen, şizofreni ve bipolar bozukluğun patofizyolojisinde yer alan nörobiyolojik bir fenomendir 32 . Beyinde, PI3K yolunun bileşenleri, sinaptik oluşumu ve plastisiteyi düzenler; dolayısıyla bu yolun bozulması sinaps disfonksiyonuna ve patolojik davranışlara yol açar 33 .…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…Most, if not all, medical conditions are associated with alterations in mitochondrial and metabolic function, including cancer [1], dementias [2], cardiovascular diseases [3], psychiatric disorders [4,5], pulmonary diseases [6] and metabolic disorders [7]. Typically, the mitochondrial dysfunction involves the suppression of mitochondrial energy production from oxidative phosphorylation (OXPHOS), coupled with increased reactive oxygen species (ROS) and the involvement of reactive cells, either systemic immune cells and/or CNS glial cells [8].…”