Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts.
During human pregnancy, placental trophoblasts differentiate and syncytialize into syncytiotrophoblasts that sustain progesterone production [1]. This process is accompanied by mitochondrial fragmentation and cristae remodeling [2], two facets of mitochondrial apoptosis, whose molecular mechanisms and functional consequences on steroidogenesis are unclear. Here we show that the mitochondria-shaping protein Optic atrophy 1 (Opa1) controls efficiency of steroidogenesis. During syncytialization of trophoblast BeWo cells, levels of the profission mitochondria-shaping protein Drp1 increase, and those of Opa1 and mitofusin (Mfn) decrease, leading to mitochondrial fragmentation and cristae remodeling. Manipulation of the levels of Opa1 reveal an inverse relationship with the efficiency of steroidogenesis in trophoblasts and in mouse embryonic fibroblasts where the mitochondrial steroidogenetic pathway has been engineered. In an in vitro assay, accumulation of cholesterol is facilitated in the inner membrane of isolated mitochondria lacking Opa1. Thus, Opa1-dependent inner membrane remodeling controls efficiency of steroidogenesis.
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
Michał
M
Wasilewski
Martina
M
Semenzato
Susanne M
SM
Rafelski
Jennifer
J
Robbins
Anna I
AI
Bakardjiev
Luca
L
Scorrano
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D034281:Dynamins; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011284:Pregnenolone; D002784:Cholesterol; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C415198:OPA1 protein, human; C498809:Opa1 protein, mouse; C110768:DNM1L protein, human; D034281:Dynamins