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.

Fig. 1

Forest plots MDD, BD, and SZ. Multivariate random-effect estimates of the SMD (95% CI, p-values) of complex I (NDU) and IV (COX) enzyme activity and subunits are shown both in numerical and graphical form. Values lower than 0 indicate that patients had lower levels than controls (CO), and vice versa for values greater than 0; the dashed vertical line at SMD = 0 indicates no effect. The size of the filled circles for each estimated SMD is proportional to the weight of the studies. P putamen, NA nucleus accumbens, GP globus pallidus

Fig. 2

Forest plots AD, PD, and AGING. Multivariate random-effect estimates of the SMD (95% CI, p-values) of complex I (NDU) and IV (COX) enzyme activity and subunits are shown both in numerical and graphical form. Values lower than 0 indicate that patients (or older (O) individuals) had lower levels than controls (CO) (or younger (Y) individuals), and vice versa for values greater than 0; the dashed vertical line at SMD = 0 indicates no effect. The size of the filled circles for each estimated SMD is proportional to the weight of the studies

Fig. 3

Forest plot Summary. Multivariate random-effect estimates of the SMD (95% CI, p-values) of complex I and IV are shown both in numerical and graphical form. SMD are ordered according to their strengths. Values lower than 0 indicate that patients (P) had lower levels than controls (CO), and vice versa for values greater than 0; the dashed vertical line at SMD = 0 indicates no effect. The size of the filled circles for each estimated SMD is proportional to the weight of the studies

Fig. 4

Schematic overview of our findings. Highlighted are the main findings of the meta-analyses for the five disorders MDD, BD, SZ, AD, PD, and normal aging. Region-specific heterogeneity means that complex levels vary from brain region to brain region (i.e., variation from ROI to ROI); tissue-specific heterogeneity indicates that complex levels vary between tissues (i.e., peripheral blood versus brain)