Marinkovic 2019 MiP2019

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Aging-related increase of cGMP disrupts mitochondrial homeostasis in Leydig cells.

Link: MiP2019

Marinkovic DZ, Sokanovic SJ, Kojic Z, Medar MLJ, Andric SA, Kostic TS (2019)

Event: MiP2019

COST Action MitoEAGLE

Since mitochondria play an essential role in initiation of testosterone biosynthesis, serve as power centers and are source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging.

Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells and these changes were correlated with progressive rise of cGMP-signaling and decline in testosterone production. To target cGMP-signaling in Leydig cells, in vivo single or long-term treatment with sildenafil (PDE5 inhibitor) and ex vivo study on isolated Leydig cells were performed.

In Leydig cells aging-induced cGMP accumulation is associated with mitochondrial dysfunction illustrated by reduced ATP levels and O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy/ autophagy (Pink1, Tfeb), fusion (Mtf1, Opa1) and increased Nfr2/NRF2. Single in vivo PDE5-inhibition, stimulated cGMP accumulation and testosterone synthesis but reduced ATP production in Leydig cells from adult, middle-aged and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP-signaling. Opposite, long-term-PDE5-inhibition decreased cGMP-signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic-treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1 and normalized Pink1 expression.

Altogether, long-term-PDE5-inhibition prevented age-related cGMP elevation, improved mitochondrial dynamics/function and testosterone production. The results pointed on cGMP-signaling in Leydig cells as target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production.


Bioblast editor: Plangger M, Tindle-Solomon L


Labels: MiParea: Respiration, mtDNA;mt-genetics, Pharmacology;toxicology  Pathology: Aging;senescence 


Tissue;cell: Genital 





Affiliations and support

Marinkovic DZ(1), Sokanovic SJ(1), Kojic Z(2), Medar MLJ(1), Andric SA(1) and Kostic TS(1)
  1. Lab Chronobiology Aging, Lab Reproductive Endocrinology Signaling, Centre Excellence CeRES, Fac Sciences, Univ Novi Sad, Novi Sad, Serbia
  2. Inst Physiology, School Medicine, Univ Belgrade, Belgrade, Serbia. - [email protected]
This work was supported by the grant no. 173057 and grant no. 451-0302807 Centre of Excellence CeRES from the Ministry of Education, Science and Technological Development, Republic of Serbia, as well as grant no. 2130 from the Autonomous Province of Vojvodina.