Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease

Abstract

Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.

Lithium and the Interplay Between Telomeres and Mitochondria in Bipolar Disorder

“…Several post-mortem studies have found both downregulation and upregulation of mitochondria-related genes; particularly those encoding complexes of the ETC ( 55 – 59 ). Moreover, decreased complex I activity has been reported in the prefrontal cortex of BD patients ( 55 ).…”

Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults

“…The proteomics analyses revealed alterations in the expression levels of five subunits of complex I in adult female hippocampus following ELS (Table 2); alterations in complex I expression/activity have been associated with the pathophysiology of several brainbased disorders (Gu et al, 2013;Holper et al, 2018) and observed in animal models following adult metabolic or chronic stress (Emmerzaal et al, 2020;Toniazzo et al, 2019). Based on the iTRAQ discoveries, we next explored whether the protein adaptations to ELS reflected altered function, using an enzyme activity assay in mitochondria isolated from the hippocampus in juveniles and adults.…”

Amyloid precursor protein‐mediated mitochondrial regulation and Alzheimer's disease

“…Furthermore, complex I subunit protein levels were found to be decreased in different areas of Alzheimer's disease and Down syndrome brain (Kim et al, ), but biochemical studies of enzymatic activity corroborating these findings are lacking in Alzheimer's disease. A meta‐analysis of complex I and complex IV findings found that only complex IV was consistently reported to be decreased in Alzheimer's disease (Holper et al, ). This analysis also showed that decreases of both complexes I and IV were consistently found in studies of human brain ageing (Holper et al, ).…”

“…A meta‐analysis of complex I and complex IV findings found that only complex IV was consistently reported to be decreased in Alzheimer's disease (Holper et al, ). This analysis also showed that decreases of both complexes I and IV were consistently found in studies of human brain ageing (Holper et al, ). It is now well established that ageing is associated with lower OXPHOS capacity in human muscle (Trounce et al, ) and, in human, non‐human primate and rodent brain (Bowling et al, ; Ferrandiz et al, ; Ojaimi et al, ).…”