The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease

Abstract

While accounting for only 2% of the body’s weight, the brain utilizes up to 20% of the body’s total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders. Mitochondria are responsible for providing the brain with most of its energetic demands, and the brain uses glucose as its exclusive energy source. Exploring the role of mitochondrial dysfunction in the etiology of psychiatric disease is a promising avenue to investigate further. Genetic analysis of mitochondrial activity is a cornerstone in understanding disease pathogenesis related to metabolic dysfunction. In concert with neuroimaging and pathological study, genetics provides an important bridge between biochemical findings and clinical correlates in psychiatric disease. Mitochondrial genetics has several unique aspects to its analysis, and corresponding special considerations. Here, we review the components of mitochondrial genetic analysis – nuclear DNA, mitochon­drial DNA, mitochondrial pathways, pseudogenes, nuclear-mitochondrial mismatch, and microRNAs – that could contribute to an observable clinical phenotype. Throughout, we highlight psychiatric diseases that can arise due to dysfunction in these processes, with a focus on schizophrenia and bipolar disorder.

Mitochondrial Dysfunction in Schizophrenia

“…[ 18,19 ] Mitochondria play an extremely important role in many neuronal functions, such as synaptic transmission, [ 20–23 ] Ca 2+ signaling, [ 24,25 ] generation of action potentials [ 26 ] and ion homeostasis, [ 27–29 ] overlapping with various aspects of neuronal functions compromised in SCZ. [ 30–32 ] Thus, we will systematically review the recent findings in metabolic/mitochondrial abnormalities observed in various SCZ research areas such as postmortem studies, imaging studies, genetic studies, induced pluripotent stem cell (iPSC) studies, animal model studies as well as the literature that point mitochondrial dysfunction as a potential therapeutic target for SCZ. [ 33,34 ]…”

Sex differences in schizophrenia: estrogen and mitochondria

“…Carly Baehr 1,2 and Marco Pravetoni 2,3 Neuropsychopharmacology (2019) 44:217-218; https://doi.org/10.1038/s41386-018-0197-3…”

“…Extensive preclinical studies have identified a series of lead vaccines selectively targeting heroin, oxycodone, hydrocodone, or fentanyl (e.g., [1][2][3]). Anti-opioid vaccines effectively reduce distribution of the target opioid to the brain, and reduce opioidinduced behavior, including drug self-administration, in mice, rats, or nonhuman primates.…”

“…Multiple studies have focused on vaccine design, including optimization of hapten and linker chemistry, choice of carrier protein and adjuvant, and development of novel carriers and delivery platforms. Effective formulations of vaccines against heroin have included the TLR9 agonist CpG [5] and liposomes containing the TLR4 agonist monophosphoryl lipid A [3]. The efficacy of an oxycodone vaccine was enhanced by shifting IgG subclass distribution through inhibition of interleukin-4 signaling, both indicating a pharmacological target for vaccine development, and granting insight into mechanisms underlying vaccine efficacy [6].…”

“…Mitochondria are the main source of energy for most cellular activities. In the brain, mitochondria are also implicated in many neuronal processes reported to be involved in SCZ pathophysiology, and mitochondrial dysfunction is emerging as a risk factor for the disorder [3]. Over 1000 mitochondrial genes are encoded by the nuclear genome, and also, mitochondria contain their own small genome (mtDNA), which is exclusively maternally inherited.…”