A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients

Morciano, Giampaolo; Pedriali, Gaia; Bonora, Massimo; Pavasini, Rita; Mikus, Elisa; Calvi, Simone; Bovolenta, Matteo; Lebiedzińska-Arciszewska, Magdalena; Pinotti, Mirko; Albertini, Alberto; Wieckowski, Mariusz R.; Giorgi, Carlotta; Ferrari, Roberto; Galluzzi, Lorenzo; Campo, Gianluca; Pinton, Paolo

doi:10.1016/j.celrep.2021.108983

Cited by 26 publications

(19 citation statements)

References 44 publications

(68 reference statements)

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“…Moreover, the tight fit of the double-chained matrix-side lipid into the c -ring establishes also hydrophobic interaction with a glycine zipper (G 20 xG 22 xG 24 xG 26 ) and this suggests that the PS rotate with the c -ring. TheGly 26 -Glu 26 mutation within the glycine-rich region of c subunits is responsible for the mitochondrial permeability transition pore (mPTP)-mediated hypoxia/reoxygenation cell death in cardiomyocytes [5] by missing the interactions of the acyl chains with the c subunits. Indeed, by the addition of negatively charged residue in the helix structure, it could favour the instability of phosphatidylserine in the c -ring and its expulsion counted in the possible mechanism of the mPTP phenomenon [6].…”

mentioning

confidence: 99%

Protein folding and unfolding: proline cis - trans isomerization at the c subunits of F 1 F O -ATPase might open a high conductance ion channel

Nesci

2022

Preprint

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The c subunits, which constitutes the c-ring apparatus of the F F -ATPase, could be the main components of the mitochondrial permeability transition pore (mPTP). The well-known modulator of the mPTP formation and opening is the cyclophilin D (CyPD), a peptidyl-prolyl cis- trans isomerase. On the loop, which connects the two hairpin α-helix of c subunit, is present the unique proline residue (Pro ) that could be a biological target of CyPD. Indeed, the proline cis- trans isomerization might provide the switch that interconverts the open/closed states of the pore by pulling out the c-ring lipid plug.

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confidence: 99%

Protein folding and unfolding: proline cis - trans isomerization at the c subunits of F 1 F O -ATPase might open a high conductance ion channel

Nesci

2022

Preprint

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“…In support of the c-ring hypothesis, the substitution of key glycine residues of subunit c increased channel conductance of the c-ring [114] and accelerated calcein release in response to ionomycin [120]. Interestingly, a naturally occurring G87E variant of subunit c increased the PTP propensity to open, exacerbating mitochondrial damage in patients with ST elevation myocardial infarction (STEMI) [121]. In support of the dimer/tetramer hypothesis, ablation of subunits e and g in yeast desensitized PTP to Ca 2+ , decreased swelling, and reduced F-ATP synthase channel conductance up to tenfold [23,122,123].…”

Section: The F-atp Synthase Porementioning

confidence: 95%

Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT

et al. 2021

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The permeability transition (PT) is an increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), a Ca2+-activated high conductance channel involved in Ca2+ homeostasis and cell death. Alterations of the PTP have been associated with many pathological conditions and its targeting represents an incessant challenge in the field. Although the modulation of the PTP has been extensively explored, the lack of a clear picture of its molecular nature increases the degree of complexity for any target-based approach. Recent advances suggest the existence of at least two mitochondrial permeability pathways mediated by the F-ATP synthase and the ANT, although the exact molecular mechanism leading to channel formation remains elusive for both. A full comprehension of this to-pore conversion will help to assist in drug design and to develop pharmacological treatments for a fine-tuned PT regulation. Here, we will focus on regulatory mechanisms that impinge on the PTP and discuss the relevant literature of PTP targeting compounds with particular attention to F-ATP synthase and ANT.

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“…In our previous publication 5 to which this short letter refers, we showed a strong and positive correlation between the mitochondrial permeability transition pore (mPTP) opening measured in fibroblasts from ST‐segment elevation myocardial infarction (STEMI) patients and reperfusion injury (RI) evaluated by cardiac magnetic resonance imaging of the same patients. Moreover, we found significant intersubject variability in mPTP opening, and the patients with hyperresponsive mPTP opening also had greater reperfusion damage.…”

Section: Introductionmentioning

confidence: 94%

“…Giampaolo Morciano 1,2 Gaia Pedriali 2 Elisa Mikus 3 Paolo Cimaglia 2 Simone Calvi 3 Rita Pavasini 4 Alberto Albertini 3 Roberto Ferrari 2 Mariusz R. Wieckowski 5 Carlotta Giorgi 1 Gianluca Campo 4 Paolo Pinton…”

Section: Conflict Of Interestmentioning

confidence: 99%

Similarities between fibroblasts and cardiomyocytes in the study of the permeability transition pore

Morciano

Pedriali

Mikus

et al. 2022

Eur J Clin Investigation

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A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients

Cited by 26 publications

References 44 publications

Protein folding and unfolding: proline cis - trans isomerization at the c subunits of F 1 F O -ATPase might open a high conductance ion channel

Protein folding and unfolding: proline cis - trans isomerization at the c subunits of F 1 F O -ATPase might open a high conductance ion channel

Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT

Similarities between fibroblasts and cardiomyocytes in the study of the permeability transition pore

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