Available online 18 May 2023, 106431

Author links open overlay panel, ABSTRACT

Steroids are important membrane components and signaling metabolites and thus are required for cellular homeostasis. All mammalian cells retain the ability to uptake and synthesize steroids. Dysregulation of steroid levels leads to profound effects on cellular function and organismal health. Hence it comes as no surprise that steroid synthesis is tightly regulated. It is well established that the main site for steroid synthesis and regulation is the endoplasmic reticulum. However, mitochondria are essential for: (1) cholesterol production (the precursor of all steroids) by exporting citrate and; (2) the products of steroidogenesis (such as mineralocorticoids and glucocorticoids). In this review, we describe the midfield player role of mitochondria in steroid synthesis and bring the idea of mitochondria actively participating in steroid synthesis regulation. A better understanding of the mitochondrial regulatory roles in steroid synthesis would open new avenues to targeted approaches aiming to control steroid levels.

Section snippetsINTRODUCTION

Mitochondria are well known for being a hub of cell signaling and regulating several metabolic pathways. It is not different for steroid synthesis where mitochondria are important midfield players regulating the synthesis of upstream precursors (citrate and cholesterol) and downstream metabolites (bile acids, steroid hormones, hydroxycholesterols, and cholesterol esters). Although steroids are fundamental for cellular homeostasis, little is known about the mechanism behind the regulation of

THE NEBULOUS ROLE OF MITOCHONDRIA IN CHOLESTEROL LEVELS REGULATION

Much more than a membrane component, cholesterol is a building block of several metabolites and the first limiting step for steroid synthesis (Ikonen, 2008). Intracellular cholesterol levels are under tight regulation and are modulated by a balance between cholesterol uptake and synthesis. The major regulator of cholesterol synthesis is the transcription factor SREBP2 (sterol regulatory element binding protein 2) which regulates the expression of the main enzymes required for cholesterol

HOW DO MITOCHONDRIA UPTAKE CHOLESTEROL?

Although cholesterol is the major non-polar lipid constituent of membranes, mitochondria are cholesterol-poor organelles (Meer et al., 2008) and are very sensitive to changes in their cholesterol content (Garcia-Ruiz et al., 2008). Accumulation of mitochondrial cholesterol triggers mitochondrial dysfunction causing energy and redox imbalance (Solsona-Vilarrasa et al., 2019). Moreover, higher levels of mitochondrial cholesterol are found in neurodegenerative disorders and myocardial ischemia

THE MITO-ER CROSSTALK FOR STEROID HORMONE SYNTHESIS

Steroid hormones, besides controlling reproduction and the development of secondary sex characteristics, allow organisms to quickly adapt to internal and external environments through signaling cascades triggered by nuclear and plasma membrane receptors. Androgens, estrogens, progesterone, glucocorticoids, and mineralocorticoids are the main steroid hormones in vertebrates and are also involved in the regulation of cell death, apoptosis, neural function, and metabolism (Billig et al., 1993,

CONCLUSION

Mitochondria play a central role in the synthesis of cholesterol and its derivatives and have been brought up as a possible target in steroid-associated diseases. However, little is known about the molecular pathways involving mitochondrial steroid metabolism regulation. Here, we have highlighted how important questions regarding the ability of mitochondria to sense and regulate steroid levels have been neglected. The existing studies support the idea of mitochondria being important midfield

Uncited reference

(YAGO et al., (1970))

Declaration of Competing Interest

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

The present work was funded by the Max Planck Institute for Biology of Ageing (MPI ageing) and RTG2550 on the "Dynamic Regulation of Cellular Protein Localization" at the University of Cologne. We would like to thank the participants of the MPI ageing writing club — Stephanie de Alcantara Fernandes, Patrick Krüger, Jiyoung Pan, Kavan Prabhu, and Robert Bayersdorf — and the members of the Pernas’ lab for the input and feedback on this work.

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