Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis.

Melissa Witzig,Steven A Brown,Imane Lejri,Amandine Grimm,Karen Schmitt,Anne Eckert,Stephan Frank

doi:10.3390/cells9102323

Melissa Witzig, Steven A Brown + Show 5 more

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https://doi.org/10.3390/cells9102323

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Abstract

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.

Highlights

Nowadays, it is well known that the circadian clock plays a paramount role in living organisms.It enables adaptation of behavior and physiology, including metabolism, body temperature, sleep–wake cycle and hormone secretion to daily environmental changes like the light/dark cycle [1,2]
Our key findings are as follows: (i) P5 and Translocator protein (TSPO) levels exhibit a circadian pattern; (ii) circadian changes in mitochondrial morphology correlate with rhythmic production of P5; and (iii) circadian variations of P5 and TSPO depend on both a functional molecular clock and functional mitochondrial dynamics
This study provided first evidence that mitochondrial fusion is an essential step of steroid production, a process which depends on protein kinase A (PKA) activity

Summary

Introduction

It is well known that the circadian clock plays a paramount role in living organisms It enables adaptation of behavior and physiology, including metabolism, body temperature, sleep–wake cycle and hormone secretion to daily environmental changes like the light/dark cycle [1,2]. The maintenance of a rhythm with a period length of about 24 h is ensured by self-sustained transcriptional–translational feedback loops [3]. This involves a complex molecular machinery resulting in the rhythmic expression of so-called clock genes, including the trans-activating components CLOCK and BMAL1 (brain and muscle ARNT-Like 1), and the trans-inhibiting components period (isoforms PER1-3) and cryptochrome (isoforms CRY1 and 2).

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