Drp1 Phosphorylation Is Indispensable for Steroidogenesis in Leydig Cells

Park, Ji Eun; Kim, Yoon Jae; Lee, Seung Gee; Kim, Ji Young; Chung, Jin Yong; Jeong, Sun Young; Koh, Hyongjong; Yun, Jeanho; Park, Hwan Tae; Yoo, Young Hyun; Kim, Jong Min

doi:10.1210/en.2019-00029

Cited by 27 publications

(33 citation statements)

References 53 publications

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“…Especially, MFN2 expression was upregulated following hormone stimulation, and its knockdown was sufficient to impair steroidogenesis, suggesting an essential role for mitochondrial fusion during steroidogenesis. More recently, Park and colleagues showed that steroid production in Leydig cells correlates with the protein kinase A (PKA)-dependent DRP1 phosphorylation (Ser 637) and mitochondrial elongation [ 33 ]. In line with these findings, our study shows for the first time a correlation between steroidogenesis and mitochondrial dynamics in brain-derived cells, in particular a cyclic production of P5, which parallels the circadian rhythm of mitochondrial fusion/fission activity.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that circadian variations of mitochondrial fusion correlate with rhythmic P5 levels, and that disturbing the molecular clock abolishes both rhythms in mitochondrial dynamics [ 12 ] and P5 levels. A link between steroidogenesis and mitochondrial dynamics was previously shown in Leydig cells with mitochondrial shaping proteins, DRP1 and MFN2, playing important roles in the regulation of steroid production [ 14 , 33 ]. Namely, PKA activation by dibutyryl cyclic AMP was shown to induce DRP1 phosphorylation at Serine 637, decreasing DRP1 mitochondrial localization and leading to mitochondrial elongation and steroidogenesis [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…A link between steroidogenesis and mitochondrial dynamics was previously shown in Leydig cells with mitochondrial shaping proteins, DRP1 and MFN2, playing important roles in the regulation of steroid production [ 14 , 33 ]. Namely, PKA activation by dibutyryl cyclic AMP was shown to induce DRP1 phosphorylation at Serine 637, decreasing DRP1 mitochondrial localization and leading to mitochondrial elongation and steroidogenesis [ 33 ]. Strikingly, DRP1 dephosphorylation at Ser 637, which leads to its translocation to mitochondria and mitochondrial fission, is regulated through clock-dependent calcineurin activation [ 34 ] with pharmacological inhibition of calcineurin increasing DRP1 phosphorylation and abrogating circadian DRP1 phosphorylation patterns [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

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Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Witzig

Grimm

Schmitt

et al. 2020

Cells

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Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Witzig

Grimm

Schmitt

et al. 2020

Cells

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“…Testicular Leydig cells nourish the spermatogonium and provide testosterone, which is important for spermatogenesis. Mitochondria are vital for Leydig cell survival and steroidogenesis (Park et al, 2019). Triptolide causes mitochondrial membrane depolarization and activates the mitochondrial apoptosis pathway in murine pituitary corticotroph tumor cells (Li et al, 2017b).…”

Section: Introductionmentioning

confidence: 99%

Triptolide Induces Leydig Cell Apoptosis by Disrupting Mitochondrial Dynamics in Rats

Chang

et al. 2021

Front. Pharmacol.

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Triptolide is widely used in the clinical treatment of various diseases. Side effects, including reproductive toxicity to male patients, limit its application. However, no detailed mechanisms or potential intervention targets have been reported. In this study, we show that triptolide activated the mitochondrial apoptosis pathway in rat testicular Leydig cells and induced apoptosis both in vivo and in vitro, which may cause hypoleydigism and impair spermatogenesis. Mechanistically, triptolide-induced dynamin-related protein 1 (Drp1) overexpression, which interfered with mitochondrial dynamic stability to activate the mitochondrial apoptosis pathway. Mdivi-1, a selective Drp1 inhibitor, partially reversed the mitochondrial dynamic disturbance and rat testicular Leydig cell apoptosis induced by triptolide. Inhibiting Drp1 over-activation may be a new strategy for mitigating the reproductive toxicity of triptolide.

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“…In cells with stimulated steroidogenesis, a tubular mitochondrial network is dominant ( 13 ) enabled by the coordinated action of mitofusion genes and proteins, including Mtn1/2 and Opa1 . Also, Leydig cell steroidogenesis is facilitated by the inhibition of mitofission due to PRKA-dependent phosphorylation of DRP1 ( 14 ). Moreover, the LH-cAMP signaling is involved in the regulation of new mitochondria generation and mitochondrial fusion/fission coupled with increased steroidogenesis and energetic function ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Growing Up Under Constant Light: A Challenge to the Endocrine Function of the Leydig Cells

et al. 2021

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The factors influencing Leydig cell maturity and the acquisition of functional capacity are incompletely defined. Here we analyzed the constant light (LL) influence on Leydig cells’ endocrine function during reproductive maturation. Rats were exposed to LL from P21 to P90. Data were collected at juvenile (P35), peri/pubertal (P42, P49), and adult (P90) stages of life. The results proved the effect of LL on rats’ physiology by changing of bimodal voluntary activity pattern into free-running. Additionally, the peripheral clock in Leydig cells changed in LL condition, indicating disturbed rhythm: the positive element (Bmal1) increased in pre-/pubertal but decreased in the adult period, while negative elements (Per2 and Reverba) were increased. The effects of LL were most prominent in puberty: pituitary genes encoding gonadotropic hormones (Cga, Lhb, Fshb) decreased; serum corticosterone increased, while serum androgens and mass of testicular and sex accessory organs reduced; markers of Leydig cells maturity/differentiation (Insl3, Lhcgr) and steroidogenesis-related genes (Scarb1, Star, Cyp11a1, Cyp17a1) decreased; the steroidogenic and energetic capacity of the Leydig cell mitochondria decreased; the mtDNA copy number reduced, and mitochondrial dynamics markers changed: fusion decreased (Opa1 and Mfn2), and mitophagy increased (Pink1). In adults, the negative effect of LL on mitochondrial function and steroidogenic capacity persists in adult Leydig cells while other parameters reached control values. Altogether, the results indicate that LL slows down Leydig cells’ maturation by reducing the endocrine and energy capacity of cells leading to the delay of reproductive development.

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Drp1 Phosphorylation Is Indispensable for Steroidogenesis in Leydig Cells

Cited by 27 publications

References 53 publications

Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Triptolide Induces Leydig Cell Apoptosis by Disrupting Mitochondrial Dynamics in Rats

Growing Up Under Constant Light: A Challenge to the Endocrine Function of the Leydig Cells

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