Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis
Melissa Witzig,
Amandine Grimm,
Karen Schmitt,
Imane Lejri,
Stephan Frank,
Steven A. Brown,
Anne Eckert
Affiliations
Melissa Witzig
Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland
Amandine Grimm
Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland
Karen Schmitt
Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland
Imane Lejri
Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland
Stephan Frank
Division of Neuropathology, Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland
Steven A. Brown
Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland
Anne Eckert
Neurobiology Lab for Brain Aging and Mental Health, Molecular & Cognitive Neuroscience, Transfaculty Research Platform, University of Basel, 4002 Basel, Switzerland
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.
