UNCORRECTED PROOF 1 Q1 Stress triggers mitochondrial biogenesis to preserve steroidogenesis in 2 Leydig cells 3 Q2 Igor A. Gak 1 , Sava M. Radovic 1 , Aleksandra R. Dukic, Marija M. Janjic, Natasa J. Stojkov-Mimic, 4 Tatjana S. Kostic, Silvana A. Andric ⁎ 5 Laboratory for Reproductive Endocrinology and Signaling (LaRES), Faculty of Sciences, University of Novi Sad, Dositeja Obradovica Sq. 2, 21000 Novi Sad, Serbia abstract 6 article info 7 Article history: 8 Received 16 February 2015 9 Received in revised form 25 May 2015 10 Accepted 29 May 2015 11 Available online xxxx 12 Keywords: 13 Mitochondrial biogenesis 14 Leydig cells 15 Stress 16 Testosterone 17 PGC1 18 Adaptability to stress is a fundamental prerequisite for survival. Mitochondria are a key component of the stress 19 response in all cells. For steroid-hormones-producing cells, including also Leydig cells of testes, the mitochondria 20 are a key control point for the steroid biosynthesis and regulation. However, the mitochondrial biogenesis in 21 steroidogenic cells has never been explored. Here we show that increased mitochondrial biogenesis is the 22 adaptive response of testosterone-producing Leydig cells from stressed rats. All markers of mitochondrial 23 biogenesis together with transcription factors and related kinases are up-regulated in Leydig cells from rats 24 exposed to repeated psychophysical stress. This is followed with increased mitochondrial mass. The expression 25 of PGC1, master regulator of mitochondrial biogenesis and integrator of environmental signals, is stimulated 26 by cAMP-PRKA, cGMP, and β-adrenergic receptors. Accordingly, stress-triggered mitochondrial biogenesis 27 represents an adaptive mechanism and does not only correlate with but also is an essential for testosterone 28 production, being both events that depend on the same regulators. Here we propose that all events induced by 29 acute stress, the most common stress in human society, provoke adaptive response of testosterone-producing 30 Leydig cells and activate PGC1, a protein required to make new mitochondria but also protector against the 31 oxidative damage. Given the importance of mitochondria for steroid hormones production and stress response, 32 as well as the role of steroid hormones in stress response and metabolic syndrome, we anticipate our result to be 33 a starting point for more investigations since stress is a constant factor in life and has become one of the most 34 significant health problems in modern societies. 35 © 2015 Published by Elsevier B.V. 36 37 38 39 40 1. Introduction 41 Stress was introduced and popularized as a medical and scientific 42 idea by Selye: “Without stress, there would be no life” [1]. “Adaptability 43 and resistance to stress are fundamental prerequisites for life, and every 44 vital organ and function participates in them” [1]. Nowadays stress is 45 established as a unifying concept to understand the interaction of or- 46 ganism with the environment and occurs when homeostasis is threat- 47 ened or perceived to be so [3]. During stress, an orchestrated adaptive 48 compensatory specific response of the organism (so-called “fight and 49 flight” response) is activated to sustain homeostasis. This includes acti- 50 vation of the sympathoadrenal, the sympathoneuronal systems, and the 51 hypothalamo–pituitary–adrenocortical (HPA) axis, but suppression of 52 hypothalamic–pituitary–gonadal (HPG) axis. The main hallmarks of 53 stress are increased levels of circulating stress mediators/hormones, in- 54 cluding corticotropin-releasing hormone (CRH), adrenocorticotropin 55 (ACTH), glucocorticoids (GCs), and the catecholamines (adrenaline, 56 noradrenaline) [3–9] as well as decrease of circulating testosterone in 57 males [10–16]. It is well recognized that stress is a major contributor 58 to the wide variety of psychosocial and physical pathological conditions 59 in humans [3,4,9]. 60 At cellular level, stressors are able to cause deleterious effects on 61 cellular infrastructure and to disturb cellular homeostasis. As a conse- 62 quence, organisms have developed the capacity to initiate a number of 63 adaptive cellular response pathways that attempt to reduce damage 64 and maintain or reestablish cellular homeostasis. Many aspects are not 65 stressor specific because cells monitor stress based on macromolecular 66 damage regardless of the type of stress that causes such damage [3,7]. 67 Epidemiological studies strongly indicate that stress-induced DNA dam- 68 age may promote ageing, tumorigenesis, neuropsychiatric conditions 69 and that a stress response pathway regulates DNA damage through 70 β2-adrenergic receptors (β2-ADRs) [17]. For all our cells, mitochondria 71 are a key component of the stress response since they are primarily 72 responsible for meeting the enormous energy demands of the “fight Biochimica et Biophysica Acta xxx (2015) xxx–xxx ⁎ Corresponding author at: Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences at University of Novi Sad, Dositeja Obradovica Square 2, 21000 Novi Sad, Serbia. E-mail address: silvana.andric@dbe.uns.ac.rs (S.A. Andric). 1 These authors contributed equally to this work. BBAMCR-17590; No. of pages: 11; 4C: 5, 6, 7, 8, 9 http://dx.doi.org/10.1016/j.bbamcr.2015.05.030 0167-4889/© 2015 Published by Elsevier B.V. Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Please cite this article as: I.A. Gak, et al., Stress triggers mitochondrial biogenesis to preserve steroidogenesis in Leydig cells, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbamcr.2015.05.030