- Epigenomics of Early Life, Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
Mitochondria play a central role in cellular energy-generating processes and are master regulators of cell life. They provide the energy necessary to reinstate and sustain homeostasis in response to stress, and to launch energy intensive adaptation programs to ensure an organism’s survival and future well-being. By this means, mitochondria are particularly apt to mediate brain programming by early-life stress (ELS) and to serve at the same time as subcellular substrate in the programming process. With a focus on mitochondria’s integrated role in metabolism, steroidogenesis and oxidative stress, we review current findings on altered mitochondrial function in the brain, the placenta and peripheral blood cells following ELS-dependent programming in rodents and recent insights from humans exposed to early life adversity (ELA). Concluding, we propose a role of the mitochondrion as subcellular intersection point connecting ELS, brain programming and mental well-being, and a role as a potential site for therapeutic interventions in individuals exposed to severe ELS.
Early life experiences can cause lasting changes in brain structure and function. This process is often referred to as developmental programming (Gluckman and Hanson, 2004) and evolves from developmental plasticity. Accordingly, a single genotype gives rise to different morphological and/or physiological phenotypes in response to experiences made during sensitive time windows.
Social experiences are among the most powerful to elicit plastic changes in the human brain and to shape structure and function of circuitries underlying social and emotional behavior (Davidson and McEwen, 2012). Early experiences in this domain are also likely to govern differences among individuals in their vulnerability or resilience to future adversity (Hochberg et al., 2011). For example, parental maltreatment (e.g., physical or emotional abuse and/or neglect) associates with early-life stress (ELS) in the infant (Murgatroyd and Spengler, 2011b; Noll and Shalev, 2018) that profoundly influences the experience-dependent maturation of structures underlying emotional and endocrine responses to stress. ELS programs hippocampal and hypothalamo-pituitary-adrenal (HPA) axis functions—integral components of the body’s stress response—and leads to increased stress responsivity in adulthood (Murgatroyd and Spengler, 2011a; Nemeroff, 2016). Likewise, maternal exposure to adversity during pregnancy impacts the quality of fetal growth and development and enhances the risk for disturbed HPA-axis regulation in the offspring, a known risk factor for various psychiatric disorders such as schizophrenia or major depression (O’Donnell and Meaney, 2017).
ELS-dependent programming of the brain takes place at different functional layers. Studies in animals have highlighted structural changes consisting of alterations in spine density, dendritic length and branching in relevant brain regions such as the hippocampus, prefrontal cortex (PFC) and amygdala (Lupien et al., 2009). Relatedly, ELS-induced programming can lead to changes in cell numbers such as diminished neurogenesis in the adult dentate gyrus (Karten et al., 2005). A recent leap forward in our understanding of the molecular basis of programming relates to the advent of epigenetics. This research field has identified mechanisms such as DNA-methylation, chromatin modifications and non-coding RNAs, among others that establish long-lasting changes in transcriptional programs governing social, emotional and neuroendocrine functions in response to ELS and thus serve as a bridge between experience and behavioral change (Murgatroyd et al., 2010; Zhang and Meaney, 2010; Hochberg et al., 2011; Hoffmann and Spengler, 2014; Cao-Lei et al., 2017).
Notwithstanding this progress, there is little doubt that additional layers of programming are likely to exist given the highly complex organization of mammalian cells. As the smallest unit of life, cells harbor different organelles that are specialized for carrying out one or more vital functions, analogous to the organs of the human body (such as the heart, lung, kidney and so forth with each organ performing a different function). Organelles such as the nucleus and golgi apparatus are typically solitary, while others such as the mitochondria, peroxisomes and lysosomes are present in numbers of hundreds to thousands (Alberts et al., 2014). While nuclear responses (i.e., changes in DNA methylation and chromatin modification) have caught mounting attention over the last years, each of these organelles and their tightly interwoven interactions are vital to cellular function and could serve as subcellular substrate in developmental programming. To explore this hypothesis, we will discuss in this review article the role of the mitochondrion as a multifunctional life-sustaining organelle and potential intersection point in ELS-induced brain programming. The principle theme that will be presently developed is how mitochondria respond and adapt to stress, and whether mitochondrial function couples to ELS-induced brain programming. At the same time, we consider the possibility that mitochondria are not only the mediator, but also the target of ELS-dependent brain programming.
We explain first origin and structure of the mitochondrion to proceed from there to the question how mitochondrial bioenergetics, steroidogenesis and reactive oxygen species (ROS) production could underpin ELS-induced programming. Following this, we examine current evidence from animal and human studies for a role of the mitochondrion to couple to and serve in ELS-dependent programming of the brain.