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Nollet 2018 IOC130

From Bioblast
Mitochondrial dysfunction in hypertrophic cardiomyopathy.

Link: Mitochondr Physiol Network 23.06

Nollet E (2018)

Event: IOC130

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, typified by left ventricular hypertrophy, diastolic dysfunction, myocyte disarray and increased risk of sudden cardiac death. HCM is the most common inherited cardiomyopathy with an estimated prevalence of 1:200 in the general population and is caused by mutations in genes encoding sarcomeric proteins, the contractile machinery of cardiomyocytes. Over 1400 mutations have been identified to be causative of HCM, the majority of which residing in thick-filament genes (MYH7, MYBPC3) and to a lesser extent in thin-filament genes (TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3). In recent years significant knowledge has been gained on the direct effects on sarcomere function of many of these mutations. However, exactly how altered sarcomere function ultimately gives rise to the HCM phenotype is a complex multifactorial process. Elucidation is warranted in order to identify and design novel therapeutic strategies tailored to different disease stages.

Currently it is hypothesized that sarcomere inefficiency, caused by mutant sarcomeric protein expression, perturbs cardiac energetics, forming the basis of the pathophysiology of HCM. Sarcomeres harboring mutant proteins are more sensitive to Ca2+, causing an increase in ATP consumption, and additionally require more ATP to generate tension compared to healthy sarcomeres. High ATP demand and consumption elevate ADP levels both in the cytosol, which contributes to diastolic dysfunction through a Ca2+-sensitizing effect on the myofilaments, and in the mitochondria, which increases oxidation of NADH and NADPH, resulting in a disrupted NADH/NAD+ balance and a reduced capacity to detoxify ROS. Furthermore, as a consequence of increased Ca2+ binding at the myofilaments, less Ca2+ is available to regenerate NADH via the Krebs cycle. Together this represents an initial mechanism underlying mitochondrial and diastolic dysfunction, occurring early before onset of HCM. Subsequently a vicious cycle ensues of increasing mitochondrial and diastolic dysfunction, leading to impaired coronary perfusion and ischemia, which further exacerbates mitochondrial dysfunction and oxidative stress, ultimately leading to cardiac remodeling[1].

Four HCM mouse models (two MYBPC3 and two TNNT2 mutants) will be deployed at 1, 4 and 12 months of age to assess the processes underlying the hypothesized sequential changes in metabolism and mitochondrial function. In addition to mitochondrial respirometry, an array of techniques will be used to perform in vivo analyses of cardiac energetic status, perfusion and diastolic performance and in vitro analyses of cardiac substrate utilization, metabolites, proteins, contractile function and cell and tissue structure. The combined knowledge obtained from these studies will improve our understanding of the pathophysiology underlying HCM and identify therapeutic targets to be applied in (pre-)symptomatic individuals.


β€’ Bioblast editor: Kandolf G β€’ O2k-Network Lab: NL Amsterdam Wuest RC


Labels: MiParea: Respiration, nDNA;cell genetics  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart 



HRR: Oxygraph-2k 


Affiliations

VUmc Medical Center, Amsterdam, The Netherlands. - [email protected]
  1. Wijnker PJM, Sequeira V, Kuster DWD, Velden JV (2018) Hypertrophic cardiomyopathy: a vicious cycle triggered by sarcomere mutations and secondary disease hits. Antioxid Redox Signal.