Maternal Inflammation During Pregnancy and Offspring Brain Development: The Role of Mitochondria

Abstract

The association between maternal immune activation (MIA) during pregnancy and risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Among the mechanistic pathways that have been described through which maternal inflammation during pregnancy may affect fetal brain development, the role of mitochondria has received little attention. In this review, the role of mitochondria as a potential mediator of the association between MIA during pregnancy and offspring brain development and risk for psychiatric disorders will be proposed. As a basis for this postulation, convergent evidence is presented supporting the obligatory role of mitochondria in brain development, the role of mitochondria as mediators and initiators of inflammatory processes, and evidence of mitochondrial dysfunction in preclinical MIA exposure models and human neurodevelopmental disorders. Elucidating the role of mitochondria as a potential mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders that have their origins in exposure to infection/immune activation during pregnancy but also offer new therapeutic targets.

Keywords: Bioenergetic function; Brain; Maternal immune activation; Mitochondria; Neurodevelopment; Oxidative stress.

Figure 1:. Conceptual Figure

Note. ROS=Reactive Oxygen Species, mtDNA=mitochondrial DNA. Maternal immune activation (MIA) can alter aspects of offspring mitochondrial structure and function including mitochondrial biogenesis/mitophagy, oxidative stress/ROS production, bioenergetic function, fission/fusion dynamics, and mtDNA quality. Mitochondrial biogenesis and mitophagy refer to the coordinated control of mitochondrial content, either through the generation of new mitochondria (mitochondrial biogenesis) or the controlled destruction/regulated turnover of mitochondria (mitophagy). Mitochondrial oxidative stress/ROS production refer to an imbalance between free radical production (mitochondrial derived) and antioxidant control of these species, which may result in damaged proteins, lipids, DNA, etc. Bioenergetic function refers to mitochondrial capacity to meet the energetic needs (e.g., ATP) of the cell or subcellular compartment. Mitochondria organelles form a dynamic reticulated network, and the subsections of this network can separate from and fuse with each other, referred to as fission/fusion dynamics. Specifically, fusion involves the tethering of two adjacent mitochondria followed by merging, of the inner and outer mitochondrial membranes, whereas fission is the opposing process of fragmentation of a mitochondrial network into two or more mitochondria. Finally, mtDNA quality refers to the level and phenotypic impact (burden) of mtDNA mutations and deletions within an individual mitochondrion or across mitochondria in a cell or tissue. As all of these aspects of mitochondrial function are crucially involved in neurodevelopmental processes, these MIA-induced alterations can affect neurodevelopment at different stages. Moreover, alterations in mitochondrial structure/function due to MIA may be programmed and, hence, can persist over the life span. Thus, in addition to the effects of MIA-induced alterations in mitochondrial function on the developing brain, these mitochondrial alterations may continue to exert long-term effects on the brain (and other systems) over the lifespan of the individual. Adapted from Nutton et al. 2011, created with BioRender.com.