Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Steroidogenic dysfunction compromises the HPG axis and reproductive function in a mouse model of mitochondrial disease (143902)

Monica Girona 1 2 , Carla Canal-Capdevila 1 2 , Celia Jimenez-Florez 1 2 , Manuel Jimenez-Puyer 3 , Veronica Sobrino 3 , Manuel Tena-Sempere 3 , Elisenda Sanz 1 2 , Albert Quintana 1 2
  1. Institut de Neurociencies, Autonomous University of Barcelona, Barcelona, Spain
  2. Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain
  3. Instituto Maimonides de Investigacion Biomedica de Cordoba , IMIBIC, Cordoba, Spain

Background:  

Mitochondrial dysfunction is associated with severe primary mitochondrial diseases that course with multisystemic alterations, including growth hormone deficiency, altered pubertal onset and impaired fertility. In particular, Leigh syndrome (LS) has been linked to endocrine alterations, suggesting dysfunction of the hypothalamic-pituitary-gonadal axis associated with mitochondrial disease.

Methods:

Developmental impairment and alterations in pubertal timing are features recapitulated in the Ndufs4KO mouse model of LS. Using this model, we performed gene expression analysis of the hypothalamus and the gonads from male and female mice at late stage of the disease. qRT-PCR approaches were complemented with histological validation of the hypothalamus and morphological studies of gonadal tissues. Puberty onset was determined by balanopreputial separation and vaginal opening inspection, and capacity to maintain ovarian cyclicity was evaluated in females through daily vaginal cytologies.

Results:

Our gene expression analyses revealed reduced Kiss1 expression in the rostral hypothalamus in a cohort of n=5-6  male (p<0.05) and female mice (p<0.01), whereas it remained unaltered in the arcuate nucleus. No differences were detected in the number of GnRH neurons. However, at the gonadal level, expression of specific steroidogenic markers was notably reduced in testicular Leydig cells (Star (p<0.0001), Cyp11a1 (p<0.05), Esr1 (p<0.01) and Prlr (p<0.001)) and ovarian theca cells (Cyp11a1 (p<0.0001) and Lhcgr (p<0.01)) of Ndufs4KO mice. The observed steroidogenic defects were also confirmed in the adrenal glands (Cyp11a1 (p<0.0001)) and brown adipose tissue (BAT) (Star (p<0.01) and Cyp11a1 (p<0.05)), while no significant changes were identified in females from a cohort of n=10-11 mice. The puberty onset determination of a cohort of n=8-10 mice revealed a significant delay in the beginning of puberty in Ndufs4KO males (p<0.01).

Conclusions:

Our results suggest that mitochondrial dysfunction disrupts gonadal steroidogenic pathways, suggesting an important contribution of peripheral mechanisms to reproductive endocrine dysfunction in mitochondrial disease.