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

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

doi:10.1016/j.celrep.2021.108983

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

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

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca²⁺) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1^G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

Original language	English
Article number	108983
Journal	Cell Reports
Volume	35
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.108983
State	Published - Apr 13 2021
Externally published	Yes

Keywords

ATP synthase
cardiovascular diseases
glycine-rich domain
ischemia
mitochondria
PTP
reperfusion injury
STEMI patients
subunit c
Myocytes, Cardiac/metabolism
Prospective Studies
Exons
Humans
Middle Aged
Oxygen/adverse effects
Male
Mitochondrial Proton-Translocating ATPases/deficiency
Calcium Channels/genetics
Base Sequence
Female
Reperfusion Injury/genetics
Gene Expression
Introns
Mitochondrial Permeability Transition Pore/metabolism
Animals
Mitochondria/genetics
Aged
Hypoxia/genetics
Mutation
ST Elevation Myocardial Infarction/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.108983

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Morciano, G., Pedriali, G., Bonora, M., Pavasini, R., Mikus, E., Calvi, S., Bovolenta, M., Lebiedzinska-Arciszewska, M., Pinotti, M., Albertini, A., Wieckowski, M. R., Giorgi, C., Ferrari, R., Galluzzi, L., Campo, G., & Pinton, P. (2021). A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients. Cell Reports, 35(2), Article 108983. https://doi.org/10.1016/j.celrep.2021.108983

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

abstract = "Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.",

keywords = "ATP synthase, cardiovascular diseases, glycine-rich domain, ischemia, mitochondria, PTP, reperfusion injury, STEMI patients, subunit c, Myocytes, Cardiac/metabolism, Prospective Studies, Exons, Humans, Middle Aged, Oxygen/adverse effects, Male, Mitochondrial Proton-Translocating ATPases/deficiency, Calcium Channels/genetics, Base Sequence, Female, Reperfusion Injury/genetics, Gene Expression, Introns, Mitochondrial Permeability Transition Pore/metabolism, Animals, Mitochondria/genetics, Aged, Hypoxia/genetics, Mutation, ST Elevation Myocardial Infarction/genetics",

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

year = "2021",

month = apr,

day = "13",

doi = "10.1016/j.celrep.2021.108983",

language = "English",

volume = "35",

journal = "Cell Reports",

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Morciano, G, Pedriali, G, Bonora, M, Pavasini, R, Mikus, E, Calvi, S, Bovolenta, M, Lebiedzinska-Arciszewska, M, Pinotti, M, Albertini, A, Wieckowski, MR, Giorgi, C, Ferrari, R, Galluzzi, L, Campo, G & Pinton, P 2021, 'A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients', Cell Reports, vol. 35, no. 2, 108983. https://doi.org/10.1016/j.celrep.2021.108983

TY - JOUR

T1 - A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients

AU - Morciano, Giampaolo

AU - Pedriali, Gaia

AU - Bonora, Massimo

AU - Pavasini, Rita

AU - Mikus, Elisa

AU - Calvi, Simone

AU - Bovolenta, Matteo

AU - Lebiedzinska-Arciszewska, Magdalena

AU - Pinotti, Mirko

AU - Albertini, Alberto

AU - Wieckowski, Mariusz R.

AU - Giorgi, Carlotta

AU - Ferrari, Roberto

AU - Galluzzi, Lorenzo

AU - Campo, Gianluca

AU - Pinton, Paolo

PY - 2021/4/13

Y1 - 2021/4/13

N2 - Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

AB - Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

KW - ATP synthase

KW - cardiovascular diseases

KW - glycine-rich domain

KW - ischemia

KW - mitochondria

KW - PTP

KW - reperfusion injury

KW - STEMI patients

KW - subunit c

KW - Myocytes, Cardiac/metabolism

KW - Prospective Studies

KW - Exons

KW - Humans

KW - Middle Aged

KW - Oxygen/adverse effects

KW - Male

KW - Mitochondrial Proton-Translocating ATPases/deficiency

KW - Calcium Channels/genetics

KW - Base Sequence

KW - Female

KW - Reperfusion Injury/genetics

KW - Gene Expression

KW - Introns

KW - Mitochondrial Permeability Transition Pore/metabolism

KW - Animals

KW - Mitochondria/genetics

KW - Aged

KW - Hypoxia/genetics

KW - Mutation

KW - ST Elevation Myocardial Infarction/genetics

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U2 - 10.1016/j.celrep.2021.108983

DO - 10.1016/j.celrep.2021.108983

M3 - Article

C2 - 33852870

AN - SCOPUS:85104069595

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 108983

ER -

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

Abstract

Keywords

UN SDGs

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