Effects of early-life stress on peripheral and central mitochondria in male mice across ages

S.R Ruigrok,K Yim,T.L Emmerzaal,B Geenen,N Stöberl,J.L Den Blaauwen,M.R Abbink,A.J Kiliaan,E.M Van Schothorst,T Kozicz,A Korosi

doi:10.1016/j.psyneuen.2021.105346

Abstract

Exposure to early-life stress (ES) increases the vulnerability to develop metabolic diseases as well as cognitive dysfunction, but the specific biological underpinning of the ES-induced programming is unknown. Metabolic and cognitive disorders are often comorbid, suggesting possible converging underlying pathways. Mitochondrial dysfunction is implicated in both metabolic diseases and cognitive dysfunction and chronic stress impairs mitochondrial functioning. However, if and how mitochondria are impacted by ES and whether they are implicated in the ES-induced programming remains to be determined.ES was applied by providing mice with limited nesting and bedding material from postnatal day (P)2-P9, and metabolic parameters, cognitive functions and multiple aspects of mitochondria biology (i.e. mitochondrial electron transport chain (ETC) complex activity, mitochondrial DNA copy number, expression of genes relevant for mitochondrial function, and the antioxidant capacity) were studied in muscle, hypothalamus and hippocampus at P9 and late adulthood (10–12 months of age).We show that ES altered bodyweight (gain), adiposity and glucose levels at P9, but not in late adulthood. At this age, however, ES exposure led to cognitive impairments. ES affected peripheral and central mitochondria in an age-dependent manner. At P9, both muscle and hypothalamic ETC activity were affected by ES, while in hippocampus, ES altered the expression of genes involved in fission and antioxidant defence. In adulthood, alterations in ETC complex activity were observed in the hypothalamus specifically, whereas in muscle and hippocampus ES affected the expression of genes involved in mitophagy and fission, respectively.Our study demonstrates that ES affects peripheral and central mitochondria biology throughout life, thereby uncovering a converging mechanism that might contribute to the ES-induced vulnerability for both metabolic diseases and cognitive dysfunction, which could serve as a novel target for intervention.

Highlights

Exposure to early-life stress (ES) programs individuals for life, leading to an increased vulnerability to develop both metabolic diseases, such as obesity, as well as cognitive dysfunction (Chugani et al, 2001; Danese and Tan, 2014)
Our study demonstrates that ES affects peripheral and central mitochondria biology throughout life, thereby uncovering a converging mechanism that might contribute to the ES-induced vulnerability for both metabolic diseases and cognitive dysfunction, which could serve as a novel target for intervention
We show that ES affects metabolic parameters at P9 and cognitive functions in adulthood, that peripheral and central mitochondria are affected by ES in an age- and tissue-dependent manner, and that muscle and hypothalamic mito chondrial functions correlate to metabolic parameters at P9, but not in adulthood

Summary

Introduction

Exposure to early-life stress (ES) programs individuals for life, leading to an increased vulnerability to develop both metabolic diseases, such as obesity, as well as cognitive dysfunction (Chugani et al, 2001; Danese and Tan, 2014). Such programming effects of ES have been shown in preclinical studies (Maniam et al, 2014; Naninck et al, 2015; Walker et al, 2017; Yam et al, 2017a, 2017b). We hypothesize that mitochondria could be such a converging entity because they are (i) the essential cellular energy power houses across most cells in our body (Nolfi-Donegan et al, 2020), (ii) critical in both responding and adapting to stress (Hoffmann and Spengler, 2018; Picard et al, 2014), and (iii) have been implicated in both metabolic disease and cognitive dysfunction (Guo et al, 2017; Khacho et al, 2017; Sivitz and Yorek, 2010)

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