Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase

• Published in: Nature communications Vol. 12; no. 1; p. 4835
• Main Authors: Carrer, Andrea, Tommasin, Ludovica, Šileikytė, Justina, Ciscato, Francesco, Filadi, Riccardo, Urbani, Andrea, Forte, Michael, Rasola, Andrea, Szabò, Ildikò, Carraro, Michela, Bernardi, Paolo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 14/34; 14/63; 38/70; 631/1647/1453; 631/45/612/1240; 631/57/1464; 631/80/642/333/1465; 82/29; 9/74; 9/97; 96/106; Ablation; Adenine; Adenosine triphosphate; ATP; ATP synthase; Channel opening; Cyclosporin A; Genetic modification; Humanities and Social Sciences; Membrane permeability; Mitochondria; Mitochondrial permeability transition pore; Molecular modelling; multidisciplinary; Nucleotides; Permeability; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25161-x

F-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ 0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ 0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway. The nature of the mitochondrial permeability transition pore (PTP) is still under debate. Here, through genetically modified F-ATP synthase, the authors show that PTP formation can be mediated by F-ATP synthase or by adenine nucleotide translocator, suggesting the existence of distinct but related permeability pathways.