Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Liu, Can; Ma, Jideng; Zhang, Jinwei; Zhao, Han; Zhu, Yanqiu; Jing, Qi; Liu, Lingyan; Zhu, Li; Jiang, Yanrui; Tang, Guiqian; Li, Xuewei; Li, Mingzhou

doi:10.3389/fgene.2019.00505

Cited by 25 publications

(20 citation statements)

References 60 publications

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“…These effects of CPZ on mitochondrial function and thymocyte apoptosis may explain why western blot and flow cytometry analyses of the thymus from CPZ-fed Gi mice identified a reduction in CD4/8 T-cell levels whereas Cx counteracted this effect, at least in part due to the hypertrophy resulting from the ablation of androgens. Supporting this, it has been suggested that androgen depletion may be involved in the regulation of mitochondrial dysfunction and toxic responses (Liu et al, 2019).…”

Section: Discussionmentioning

confidence: 92%

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Almuslehi

Sen

Shortland

et al. 2020

Front. Cell. Neurosci.

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Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8 + T-cell recruitment into the CNS. The increased CD8 + T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx+0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an "inside-out" immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

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Section: Discussionmentioning

confidence: 92%

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Almuslehi

Sen

Shortland

et al. 2020

Front. Cell. Neurosci.

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“…A correlation between PGC-1α methylation and mtDNA copy number is established with numerous studies reporting that PGC-1α promoter methylation is consistently associated with reduced mRNA expression and lower mtDNA copy numbers in a range of different tissues (Lillycrop et al, 2005;Ling et al, 2008;Barrès et al, 2009;Sookoian et al, 2010;Chen et al, 2012;Gillberg et al, 2014;Heinonen et al, 2015;Kelstrup et al, 2016;Kresovich et al, 2018;Liu et al, 2019;Petrie et al, 2020;Yang et al, 2020). These include studies that focused on both neurological (Yang et al, 2020) and metabolic disorders (Sookoian et al, 2010;Zhao et al, 2017;Kresovich et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Front. Cell Dev. Biol.

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Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

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“…Interestingly, in a rodent model, synergistic activation of two of these markers, namely TFAM and FOXC2, enhanced adipose tissue expression of core proteins of mitochondrial fusion (MFN1, MFN2, and OPA1) consequently leading to a lean and insulin-sensitive phenotype [63][64][65][66]. Noteworthy, given that TFAM, one of the most important mitochondrial DNA transcription factors [67][68][69], contains AR-responsive elements, it is now considered a relevant AR target gene through which testosterone might regulate mitochondrial homeostasis [70]. In line with this evidence, a recent study demonstrated that AR, besides being nuclear, also localizes into mitochondria, where it modulates some of the nongenomic effects of androgens [71].…”

Section: Discussionmentioning

confidence: 99%

Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men

Maseroli

Comeglio

Corno

et al. 2020

J Endocrinol Invest

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Purpose In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. Methods Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. Results In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. Conclusions The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014

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Testosterone Deficiency Caused by Castration Modulates Mitochondrial Biogenesis Through the AR/PGC1α/TFAM Pathway

Cited by 25 publications

References 60 publications

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men

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