title: Mitochondrial fusion is essential for steroid biosynthesis.
abstract: Although the contribution of mitochondrial dynamics (a balance in fusion/fission events and changes in mitochondria subcellular distribution) to key biological process has been reported, the contribution of changes in mitochondrial fusion to achieve efficient steroid production has never been explored. The mitochondria are central during steroid synthesis and different enzymes are localized between the mitochondria and the endoplasmic reticulum to produce the final steroid hormone, thus suggesting that mitochondrial fusion might be relevant for this process. In the present study, we showed that the hormonal stimulation triggers mitochondrial fusion into tubular-shaped structures and we demonstrated that mitochondrial fusion does not only correlate-with but also is an essential step of steroid production, being both events depend on PKA activity. We also demonstrated that the hormone-stimulated relocalization of ERK1/2 in the mitochondrion, a critical step during steroidogenesis, depends on mitochondrial fusion. Additionally, we showed that the SHP2 phosphatase, which is required for full steroidogenesis, simultaneously modulates mitochondrial fusion and ERK1/2 localization in the mitochondrion. Strikingly, we found that mitofusin 2 (Mfn2) expression, a central protein for mitochondrial fusion, is upregulated immediately after hormone stimulation. Moreover, Mfn2 knockdown is sufficient to impair steroid biosynthesis. Together, our findings unveil an essential role for mitochondrial fusion during steroidogenesis. These discoveries highlight the importance of organelles' reorganization in specialized cells, prompting the exploration of the impact that organelle dynamics has on biological processes that include, but are not limited to, steroid synthesis.
authors.affiliation: Instituto de Investigaciones Biomédicas (INBIOMED), Department of Human Biochemistry, School of Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Duarte
authors.forename: Cecilia
authors.initials: C
authors.lastname: Poderoso
authors.forename: Mariana
authors.initials: M
authors.lastname: Cooke
authors.forename: Gastón
authors.initials: G
authors.lastname: Soria
authors.forename: Fabiana
authors.initials: F
authors.lastname: Cornejo Maciel
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gottifredi
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Podestá
mesh_terms: D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000494:pharmacology / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053140:Organelle Shape; D011374:Progesterone / Q000096:biosynthesis*; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D061209:Proton Ionophores / Q000494:pharmacology; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D006063:Chorionic Gonadotropin; D007546:Isoquinolines; D024101:Mitochondrial Proteins; D061209:Proton Ionophores; D013449:Sulfonamides; D011374:Progesterone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide