TY  - JOUR
A1  - Wasmus, Christina
A1  - Dudek, Jan
T1  - Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies
JF  - Life
N2  - The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.
KW  - cardiolipin
KW  - mitochondria
KW  - Barth syndrome
KW  - Sengers syndrome
KW  - respiratory chain
KW  - Dilated Cardiomyopathy with Ataxia
KW  - cardiomyopathy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219286
SN  - 2075-1729
VL  - 10
IS  - 11
ER  - 
TY  - JOUR
A1  - Dudek, Jan
A1  - Maack, Christoph
T1  - Mechano-energetic aspects of Barth syndrome
JF  - Journal of Inherited Metabolic Disease
N2  - Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation-contraction coupling, calcium (Ca\(^{2+}\)) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca\(^{2+}\) influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca\(^{2+}\) uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies.
KW  - Barth syndrome
KW  - respiratory chain
KW  - reactive oxygen species
KW  - cardiolipin
KW  - mitochondria
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257512
VL  - 45
IS  - 1
ER  -