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Cited by 79Mitochondrial Function and PathologySteroid Chemistry and BiochemistryCaveolin-1 and cellular processes

Mitochondrial fusion and ERK activity regulate steroidogenic acute regulatory protein localization in mitochondria

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Duarte, Alejandra, Castillo, Ana Fernanda, Podestá, Ernesto J., Poderoso, Cecilia·2014·PLoS ONE
DOI 10.1371/journal.pone.0100387PMC PMC4063759
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Abstract

The rate-limiting step in the biosynthesis of steroid hormones, known as the transfer of cholesterol from the outer to the inner mitochondrial membrane, is facilitated by StAR, the Steroidogenic Acute Regulatory protein. We have described that mitochondrial ERK1/2 phosphorylates StAR and that mitochondrial fusion, through the up-regulation of a fusion protein Mitofusin 2, is essential during steroidogenesis. Here, we demonstrate that mitochondrial StAR together with mitochondrial active ERK and PKA are necessary for maximal steroid production. Phosphorylation of StAR by ERK is required for the maintenance of this protein in mitochondria, observed by means of over-expression of a StAR variant lacking the ERK phosphorylation residue. Mitochondrial fusion regulates StAR levels in mitochondria after hormone stimulation. In this study, Mitofusin 2 knockdown and mitochondrial fusion inhibition in MA-10 Leydig cells diminished StAR mRNA levels and concomitantly mitochondrial StAR protein. Together our results unveil the requirement of mitochondrial fusion in the regulation of the localization and mRNA abundance of StAR. We here establish the relevance of mitochondrial phosphorylation events in the correct localization of this key protein to exert its action in specialized cells. These discoveries highlight the importance of mitochondrial fusion and ERK phosphorylation in cholesterol transport by means of directing StAR to the outer mitochondrial membrane to achieve a large number of steroid molecules per unit of StAR.

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  • StAR is a direct target of hormonally stimulated cellular kinase signaling pathways, including the PKA and ERK kinase pathways.

    “Moreover, a number of studies have demonstrated that StAR is a direct target of hormonally stimulated cellular kinase signaling pathways, including the protein kinase A (PKA) and ERK kinase pathways (94, 135, 136).”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [136]

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Authors
Duarte, A., Castillo, A. F., Podestá, E. J., & Poderoso, C.
Affiliations
Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
Corresponding author
Poderoso, Cecilia
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-06-19
Volume
9
Issue
6
Pages
e100387
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0100387
PMC
PMC4063759
OpenAlex
W2085757254
Cited by
79
References
8
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 14 · 2015: 6 · 2014: 1
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • Greater South Information System
Funders
  • Consejo Nacional de Investigaciones Científicas y Técnicas
  • Universidad de Buenos Aires (CONICET)
  • Agencia Nacional de Promoción Científica y Tecnológica (CONICET)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
steroidogenic acute regulatory protein, stars, mitochondrial fusion, mitofusin 2, ERK1/2 phosphorylation, protein localization, steroidogenesis, cholesterol transport, mitochondrial outer membrane, protein kinase A, Leydig cells, mitochondrial protein phosphorylation
MeSH terms
Steroidogenic Acute Regulatory Protein, Cyclic AMP, Animals, Cell Line, Gene Expression Regulation, Male, Mitochondria, Models, Biological, Phosphoproteins, Phosphorylation, Phosphoserine, RNA, Messenger, Steroids, Transcription, Genetic, Cyclic AMP-Dependent Protein Kinases, GTP Phosphohydrolases, Protein Transport, Extracellular Signal-Regulated MAP Kinases, Mice, Mitochondrial Dynamics

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