Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

Abstract

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

Relationships between Uncoupling Protein Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia

“…ROS are discussed in the regulation of thermogenesis [ 20 , 21 , 22 ]. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system [ 78 ]. According to some researchers, revealing the link between mitochondrial biogenesis and the KYN metabolic system may be a promising option [ 78 ].…”

“…Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system [ 78 ]. According to some researchers, revealing the link between mitochondrial biogenesis and the KYN metabolic system may be a promising option [ 78 ]. Experimental data have shown that ROS production is increased in mice with knockout UCP3 [ 79 , 80 ].…”

Alterations of the Composition and Neurometabolic Profile of Human Gut Microbiota in Major Depressive Disorder

“…Mechanisms that have been found to be linked to depression also include a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis [ 6 ], immune-inflammatory and oxidative pathways [ 7 ], altered vagus nerve tone [ 8 ], and imbalance between neural excitatory and inhibitory signaling [ 9 ]. Other factors that can lead to the development of depression includes chronic and acute stress [ 10 ], depletion of monoamines [ 11 ], poor nutrition [ 12 ], mitochondrial dysfunction [ 13 ], disrupted metabolism [ 14 ], environmental factors and epigenetics [ 15 ], infection [ 16 ], levels of sex hormones [ 17 ], etc. Inflammation is now considered one of the primary pathologies that lead to depression.…”

“…Recently, a novel kynurenine pathway (KP) has drawn attention in the cytokine theory [ 10 ]. Pro-inflammatory cytokines activate the KP by affecting tryptophan (TRP) metabolism and releasing neurotoxins, which can either reduce serotonin production or promote serotonin reuptake [ 13 ]. The COVID-19 pandemic has led to long-term psychiatric symptoms, possibly due to an immunological reaction to the virus itself, as well as fundamental changes in life associated with the pandemic.…”

Corpus Callosum Microstructural Tract Integrity Relates to Longer Emotion Recognition Reaction Time in People with Schizophrenia

“…According to the National Institute of Mental Health (NIMH) in 2021, the international prevalence rates are reportedly between 0.33–0.75%. There are various contributing factors to the development of schizophrenia, including genetic predisposition and polygenic risk [ 2 ], neuroinflammation [ 3 ], decreased synaptic spine density [ 4 ], cannabis use [ 5 ], psychosocial influences and reduced stress resilience [ 6 ], adverse childhood experiences and trauma [ 7 ], diminished anti-inflammatory response alongside reduced lipid metabolism [ 8 ], mitochondrial stress resilience [ 9 ], and gene–environment interaction effects [ 10 ]. In line with this, the diathesis–stress model may be a potential hypothesis accounting for the overall development of the disorder [ 11 ].…”