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Paolo Bernardi, MD - "The dual life of mitochondrial F-ATP synthase"

Full Professor, Department of Biomedical Sciences, University of Padova, Italy
When Oct 22, 2019
from 12:00 PM to 01:00 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Short CV

Mitochondria can undergo a Ca2+-dependent increase of inner membrane permeability (the permeability transition, PT) to solutes with mass up to about 1.5 kDa. The PT, which is favored by oxidative stress and inhibited by matrix H+, Mg2+ and adenine nucleotides, is mediated by opening of a high-conductance channel, the PT pore (PTP) or mitochondrial megachannel (MMC). The molecular identity of the MMC/ PTP remains a point of controversy, in particular about whether it can originate from a Ca2+-dependent conformational change of the energy-conserving  F1FO (F)-ATP synthase. To address this question we have used two complementary strategies. In the first, we have produced selective mutants of F-ATP synthase and assessed the consequences of the mutations on Ca2+-sensitivity, inhibition by H+ and modulation by specific reagents of the MMC/PTP. In the second strategy, we have employed highly pure and stable F-ATP synthase from large-scale preparations from bovine hearts. When the latter was incorporated into preformed liposomes, ATP hydrolysis generated a H+ gradient that could be dissipated by Ca2+. Ca2+ elicited currents matching those of the MMC/PTP when the same preparation was incorporated into planar lipid bilayers. Currents were fully reversible, and were inhibited by Mg2+ and adenine nucleotides but not by inhibitors of the adenine nucleotide translocase and of the voltage-dependent anion channel. Taken together our findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca2+ can transform the energy-conserving F-ATP synthase into an energy-dissipating device. I will discuss recent advances that may resolve apparent discrepancies in the literature, and hopefully provide a frame to understand this complex and fascinating problem of mitochondrial biology.


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