Developmental programming of mitochondrial biology: a conceptual framework and review

Abstract

Research on mechanisms underlying the phenomenon of developmental programming of health and disease has focused primarily on processes that are specific to cell types, organs and phenotypes of interest. However, the observation that exposure to suboptimal or adverse developmental conditions concomitantly influences a broad range of phenotypes suggests that these exposures may additionally exert effects through cellular mechanisms that are common, or shared, across these different cell and tissue types. It is in this context that we focus on cellular bioenergetics and propose that mitochondria, bioenergetic and signalling organelles, may represent a key cellular target underlying developmental programming. In this review, we discuss empirical findings in animals and humans that suggest that key structural and functional features of mitochondrial biology exhibit developmental plasticity, and are influenced by the same physiological pathways that are implicated in susceptibility for complex, common age-related disorders, and that these targets of mitochondrial developmental programming exhibit long-term temporal stability. We conclude by articulating current knowledge gaps and propose future research directions to bridge these gaps.

Keywords: bioenergetics; developmental programming; fetal programming; maternal–fetal–placental biology; mitochondria.

Figure 1.

Adverse/suboptimal maternal or grandmaternal gestational exposures can alter the essential aspects of offspring mitochondrial function in the following ways: (i) impaired oxidative phosphorylation; (ii) decreased mitochondrial content; (iii) increased ROS and impaired REDOX balance; and (iv) impaired mtDNA quality. There are multiple measures representing specific aspects of mitochondrial function, as depicted in this figure. Collectively, mitochondria can send out stress-related signals, such as increased ROS or Ca²⁺, decreased ATP, altered mitochondrial metabolic intermediates (e.g. NAD⁺, acetyl-CoA) and mito-peptides, that can alter nDNA gene expression or modify the epigenome via chromatin (methylation or acetylation of the DNA and/or histones), which can further alter mitochondrial function and bioenergetic capacity. In particular, mitochondrially generated ROS can have a major impact on this process. Nuclear and mitochondrial function are linked, such that one system regulates the other, and vice versa. The collective effect of these processes enables and regulates the flow of matter/energy in metabolic networks, and these regulate cellular information through signalling and transcriptional regulatory networks, which regulate the flow of energy. (Online version in colour.)