Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Witzig, Melissa; Grimm, Amandine; Schmitt, Karen; Lejri, Imane; Frank, Stephan; Brown, Steven A.

doi:10.3390/cells9102323

Cited by 9 publications

(3 citation statements)

References 38 publications

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“…Since the synthesis of pregnenolone is the first step of steroidogenesis taking place within mitochondria [ 51 ], our finding supports the thesis of crosstalk between mitochondrial function and circadian cycles [ 52 , 53 ]. Alterations in the synthesis of pregnenolone might produce consequences in the levels of hormones downstream of the steroid hormone cascade (e.g., testosterone and estrogens).…”

Section: Discussionsupporting

confidence: 83%

Alterations in Pregnenolone and Testosterone Levels in Male Shift Workers

Bracci

Zingaretti

Martelli

et al. 2023

IJERPH

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Steroid hormone levels are closely related to the endogenous circadian rhythm induced by sleep–wake and dark–light cycles. Shift work that disrupts the circadian rhythm may influence the levels of steroid hormones. The association between shift work and alterations in female sex steroid hormone levels has been studied, but little is known about testosterone and its precursor pregnenolone levels in male shift workers. The present study investigated serum pregnenolone and testosterone levels in a group of shift and daytime male workers. All participants were sampled at the beginning of the morning shift. Lower levels of serum pregnenolone and total testosterone were found in the shift workers compared to the daytime workers. Variations in pregnenolone levels may have consequences for well-being, and they might produce consequences for the levels of hormones downstream of the steroid hormone cascade, such as testosterone. The low levels of testosterone found in shift workers demonstrate the perturbative effect of shift work on testosterone serum levels, which may be independent and/or related to pregnenolone synthesis.

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Section: Discussionsupporting

confidence: 83%

Alterations in Pregnenolone and Testosterone Levels in Male Shift Workers

Bracci

Zingaretti

Martelli

et al. 2023

IJERPH

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“…Of note, MFN2 is also involved in mitochondrial fusion and knocking down MFN2 leads to mitochondrial fragmentation. We previously showed that MFN2 KD disturbs the circadian variations of mitochondrial fusion/fission and circadian variations of pregnenolone synthesis, without affecting pregnenolone level per se (Witzig et al , 2020 ). These data suggested that it is the dynamic process of mitochondrial fusion that plays a role in mitochondrial steroidogenesis.…”

Section: Discussionmentioning

confidence: 99%

ER‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein

et al. 2023

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Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria‐associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER‐mitochondria interactions via vesicle‐associated membrane protein‐associated protein (VAPB)—protein tyrosine phosphatase‐interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol‐related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB–PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau‐induced impairments in the ER‐mitochondria interaction and cholesterol metabolism.

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“…StAR and transport protein (TSPO) are the main components mediating the transport of cholesterol into the mitochondria. Current research indicates that the synthesis of pregnenolone, a precursor to all other steroids, is regulated by the circadian clock, which in turn depends on diurnal changes in mitochondrial dynamics [ 164 ]. Mitochondrial fusion correlates with pregnenolone production, and disturbance of the mechanism regulating the circadian cycle disturbs both the rhythm of changes in the dynamics of mitochondria and the synthesis of pregnenolone.…”

Section: Sex Hormone Regulation Of Oxidative Phosphorylation In the Brainmentioning

confidence: 99%

Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease

Głombik

Detka

Budziszewska

2021

Cells

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The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood–brain barrier and bind to their specific receptors on neurons and glial cells. Hormones ensure proper communication between the brain and the body by activating adaptive mechanisms necessary to withstand and react to changes in internal and external conditions by regulating neuronal and synaptic plasticity, neurogenesis and metabolic activity of the brain. The influence of hormones on energy metabolism and mitochondrial function in the brain has gained much attention since mitochondrial dysfunctions are observed in many different pathological conditions of the central nervous system. Moreover, excess or deficiency of hormones is associated with cell damage and loss of function in mitochondria. This review aims to expound on the impact of hormones (GLP-1, insulin, thyroid hormones, glucocorticoids) on metabolic processes in the brain with special emphasis on oxidative phosphorylation dysregulation, which may contribute to the formation of pathological changes. Since the brain concentrations of sex hormones and neurosteroids decrease with age as well as in neurodegenerative diseases, in parallel with the occurrence of mitochondrial dysfunction and the weakening of cognitive functions, their beneficial effects on oxidative phosphorylation and expression of antioxidant enzymes are also discussed.

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Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

Cited by 9 publications

References 38 publications

Alterations in Pregnenolone and Testosterone Levels in Male Shift Workers

Alterations in Pregnenolone and Testosterone Levels in Male Shift Workers

ER‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein

Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease

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