TY  - THES
A1  - Bertero, Edoardo
T1  - Mechano-energetic uncoupling in Barth syndrome cardiomyopathy
T1  - Mechano-energetische Entkopplung bei der Barth Syndrom Kardiomyopathie
N2  - In this Doctoral Thesis we investigated the consequences of perturbed mitochondrial calcium handling in the context of a rare human disease, Barth syndrome, in which the altered phospholipid composition of the inner mitochondrial membrane affects the structural organization of several protein complexes, including the mitochondrial calcium uniporter. We discovered that loss of the mitochondrial calcium uniporter in cardiac, but not skeletal muscle mitochondria hinders the calcium-induced adaptation of mitochondrial oxidative metabolism during workload transitions. This mechano-energetic uncoupling impairs the physiological increase in contractile force during physical exercise and might predispose Barth syndrome patients to the development of arrhythmias.
N2  - Diese Doktorarbeit umfasst vier Studien, deren verbindendes Thema die Rolle von Calcium (Ca2+) als Verbindung zwischen elektromechanischer Kopplung und mitochondrialem oxidativen Metabolismus im Herzen unter physiologischen und pathologischen Bedingungen ist. Dieser Prozess wird als mechano-energetische Kopplung bezeichnet. Während eine übermäßige Ca2+ Aufnahme in Mitochondrien katastrophale Folgen für die oxidative Phosphorylierung hat und zum Zelltod führt, stimuliert die physiologische Ca2+-Aufnahme über den mitochondrialen Ca2+ uniporter (MCU) die Krebs-Zyklus abhängige Erzeugung von Reduktionsäquivalenten, die sowohl die Atmungskette als auch die mitochondrialen Antioxidationssysteme antreiben, und spielt somit eine wesentliche Rolle sowohl für die ATP Produktion als auch für die Eliminierung reaktiver Sauerstoffspezies (ROS). ...
KW  - Barth syndrome
KW  - Cardiomyopathy
KW  - Mitochondria
KW  - Calcium
KW  - Cardiolipin
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255176
ER  - 
TY  - JOUR
A1  - Sacchetto, Claudia
A1  - Sequeira, Vasco
A1  - Bertero, Edoardo
A1  - Dudek, Jan
A1  - Maack, Christoph
A1  - Calore, Martina
T1  - Metabolic Alterations in Inherited Cardiomyopathies
JF  - Journal of Clinical Medicine
N2  - The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
KW  - inherited cardiomyopathies
KW  - mitochondria
KW  - cardiac metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193806
SN  - 2077-0383
VL  - 8
IS  - 12
ER  - 
TY  - JOUR
A1  - Schwemmlein, Julia
A1  - Maack, Christoph
A1  - Bertero, Edoardo
T1  - Mitochondria as therapeutic targets in heart failure
JF  - Current Heart Failure Reports
N2  - Purpose of Review
We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production.

Recent Findings
Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes.

Summary
The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.
KW  - mitochondria
KW  - heart failure
KW  - reactive oxygen species
KW  - MitoQ
KW  - elamipretide
KW  - SGLT2 inhibitors
KW  - cardiac metabolism
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324015
VL  - 19
IS  - 2
ER  - 
TY  - JOUR
A1  - Ameri, Pietro
A1  - Schiattarella, Gabriele Giacomo
A1  - Crotti, Lia
A1  - Torchio, Margherita
A1  - Bertero, Edoardo
A1  - Rodolico, Daniele
A1  - Forte, Maurizio
A1  - Di Mauro, Vittoria
A1  - Paolillo, Roberta
A1  - Chimenti, Cristina
A1  - Torella, Daniele
A1  - Catalucci, Daniele
A1  - Sciarretta, Sebastiano
A1  - Basso, Cristina
A1  - Indolfi, Ciro
A1  - Perrino, Cinzia
T1  - Novel basic science insights to improve the management of heart failure: Review of the working group on cellular and molecular biology of the heart of the Italian Society of Cardiology
JF  - International Journal of Molecular Sciences
N2  - Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding novel treatments. Here, we discuss recent basic science insights that encompass major areas of translational research in HF and have high potential clinical impact.
KW  - heart failure
KW  - basic
KW  - translational
KW  - research
KW  - mechanisms
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285085
SN  - 1422-0067
VL  - 21
IS  - 4
ER  - 
TY  - JOUR
A1  - Wagner, Michael
A1  - Bertero, Edoardo
A1  - Nickel, Alexander
A1  - Kohlhaas, Michael
A1  - Gibson, Gary E.
A1  - Heggermont, Ward
A1  - Heymans, Stephane
A1  - Maack, Christoph
T1  - Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart
JF  - Basic Research in Cardiology
N2  - In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H\(_2\)O\(_2\) by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H\(_2\)O\(_2\) elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in skeletal muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H\(_2\)O\(_2\) emission in cardiac mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H\(_2\)O\(_2\) emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H2O2 emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H\(_2\)O\(_2\)-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H2O2 emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H\(_2\)O\(_2\)-eliminating capacity increases H\(_2\)O\(_2\) emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H\(_2\)O\(_2\) emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H\(_2\)O\(_2\) elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.
KW  - mitochondria
KW  - α-Ketoglutarate dehydrogenase
KW  - reactive oxygen species
KW  - nicotinamide nucleotide transhydrogenase
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234907
SN  - 0300-8428
VL  - 115
ER  -