Abstract
Mammalian mitochondrial biogenesis is a complex process involving mitochondrial proliferation and differentiation. Mitochondrial DNA transcription factor A (TFAM), which encodes a major component of a protein-mitochondrial DNA (mtDNA) complex, is regulated by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Testosterone is the primary male sex hormone and plays an increasingly important role in mammalian development through its interaction with androgen receptor (AR). However, the function of AR in mitochondrial biogenesis induced by testosterone deficiency has not been investigated. Here, we explored the molecular mechanism underlying the effect of testosterone deficiency on mitochondrial biogenesis using a Yorkshire boar model. Testosterone deficiency caused by castration induced changes in mtDNA copy numbers in various tissues, and AR showed the opposite tendency to that of mtDNA copy number, particularly in adipose tissues and muscle tissues. In addition, castration weakened the correlation of PGC1α and mtDNA copy number, while AR and TFAM showed a relatively high correlation in both control and castrated pigs. Furthermore, luciferase assays revealed that AR binds to potential AR elements in the TFAM promoter to promote TFAM expression. Taken together, testosterone may be involved in the pathway linking PGC1α to mitochondrial biogenesis through the interaction between AR and TFAM.
Highlights
As vital organelles in eukaryotic cells, mitochondria are involved in various biological processes, including cell energy metabolism (Aversa et al, 2017), calcium ion homeostasis (Detmer and Chan, 2007), and cell apoptosis (Teslaa et al, 2016)
Our results showed that testosterone deficiency induced dramatic changes in mitochondrial DNA (mtDNA) copy numbers in different tissues. mtDNA copy number is regulated by many factors, including mitochondrial biogenesis and mitochondrial autophagy (Gaziev et al, 2014; Santos et al, 2014)
The fold change in correlation coefficient of PGC1α was higher than that of Pink1 and Bnip3, which indicated that testosterone deficiency more significantly weakened the effects of PGC1α on mitochondrial biogenesis. These results suggested that testosterone deficiency affected the mtDNA copy numbers by modulating mitochondrial homeostasis-associated genes, in mitochondrial biogenesis, which may be through weakening the links between PGC1a and mtDNA copy numbers
Summary
As vital organelles in eukaryotic cells, mitochondria are involved in various biological processes, including cell energy metabolism (Aversa et al, 2017), calcium ion homeostasis (Detmer and Chan, 2007), and cell apoptosis (Teslaa et al, 2016). Accumulating evidence showed that mitochondrial dysfunction is closely related to human mtDNA-mutation diseases including skeletal muscle atrophy (Theilen et al, 2016), prostate cancer (Zhou et al, 2014), cardiovascular disease (Tsutsui et al, 2008) and breast cancer (Thyagarajan et al, 2013), which are associated with variations in mtDNA copy number. This suggests the crucial role of mitochondrial homoeostasis in maintaining a variety of normal physiological processes (Eskiocak et al, 2016). The tissue profile of mtDNA copy numbers and mitochondrial homoeostasis-associated gene expressions in mammals has not been well-studied
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