Genetic Architecture of Heart Mitochondrial Proteome influencing Cardiac Hypertrophy

Krishnan, Karthickeyan Chella; Hachem, Elie-Julien El; Carroll, Luke; Vegas, Alexis Diaz; Light, Christine; Pan, Calvin; Kaczor‐Urbanowicz, Karolina Elżbieta; Shravah, Varun; Anum, Diana; Pellegrini, Matteo; Lee, Chi Fung; Seldin, Marcus M.; Parker, Benjamin L.; James, David E.; Lusis, Aldons J.

doi:10.1101/2022.08.24.505177

Cited by 2 publications

(1 citation statement)

References 80 publications

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“…39 disruption of complex I alone is sufficient to cause myocardial dysfunction, independent of ROS-dependent pathways, highlighting its pivotal role in bioenergetic processes. 41 Our study findings indicate:…”

Section: Discussionmentioning

confidence: 63%

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

Zhang,

Zhou,

Meng

et al. 2024

J Cellular Molecular Medi

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Histidine triad nucleotide‐binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2‐overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload‐induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

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Section: Discussionmentioning

confidence: 63%

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

Zhang,

Zhou,

Meng

et al. 2024

J Cellular Molecular Medi

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The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases

Jurrjens

Seldin

Giles

et al. 2023

eLife

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Cardiometabolic diseases encompass a range of interrelated conditions that arise from underlying metabolic perturbations precipitated by genetic, environmental, and lifestyle factors. While obesity, dyslipidaemia, smoking, and insulin resistance are major risk factors for cardiometabolic diseases, individuals still present in the absence of such traditional risk factors, making it difficult to determine those at greatest risk of disease. Thus, it is crucial to elucidate the genetic, environmental, and molecular underpinnings to better understand, diagnose, and treat cardiometabolic diseases. Much of this information can be garnered using systems genetics, which takes population-based approaches to investigate how genetic variance contributes to complex traits. Despite the important advances made by human genome-wide association studies (GWAS) in this space, corroboration of these findings has been hampered by limitations including the inability to control environmental influence, limited access to pertinent metabolic tissues, and often, poor classification of diseases or phenotypes. A complementary approach to human GWAS is the utilisation of model systems such as genetically diverse mouse panels to study natural genetic and phenotypic variation in a controlled environment. Here, we review mouse genetic reference panels and the opportunities they provide for the study of cardiometabolic diseases and related traits. We discuss how the post-GWAS era has prompted a shift in focus from discovery of novel genetic variants to understanding gene function. Finally, we highlight key advantages and challenges of integrating complementary genetic and multi-omics data from human and mouse populations to advance biological discovery.

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Genetic Architecture of Heart Mitochondrial Proteome influencing Cardiac Hypertrophy

Cited by 2 publications

References 80 publications

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases

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