Pathological Effect of Metabolic Stress Induces Mitochondria Dysfunction and Heart Failure, Mouse Model

 Introduction (1000 words)

• Write about metabolic heart disease.
• Important of mitochondria for heart.
• Explain some important mechanisms including fatty acid, TCA, and oxidative phosphorylation (OXPHOX) in heart to generate ATP by mitochondria.
• Aim of study:
(1) Establish and optimise mouse models of heart failure (HF) that recapitulate the characteristic features associated with human (HF)
(2) characterise the phenotype of HF in mouse models at the level of cardiac and lung function and structural remodelling.
(3) Investigate mitochondria morphological and functional changes associated with these models.
(4) Assess mitochondria biogenesis and OXPHOS genes associated with these mice model

• Implication (important) of study: write about target mitochondrial dysfunction for as pharmacological therapy.

 Literature review (3000 words)

• Effect of metabolic stress including high fat diet (obesity), DM, and hypertension on mitochondria ultra-structure and function, which can lead to heart failure

Important notes:
o Focus on clinical and animal specially mice experiment. Please present mouse models and results of study that you review to cover all points in clear way.
o Change on mitochondria OXPHOS complex function and ATP generation.
o Change on mitochondria ultra-structure in transmission electron microscope (TEM). See these articles for more information https://doi.org/10.3389/fragi.2021.670267
https://doi.org/10.1111/bph.14499

• Possible effect of trimethylamine N-oxide (TMAO) to induce metabolic stress, mitochondria dysfunction and heart failure throw mitochondria dysfunction.

Important notes:
o What is TMAO.
o Source of TMAO.
o TMAO and cardiovascular disease in clinical and animal experiment. Please present results of study that you review about TMAO and cardiovascular disease in clear way.

• Chang in mitochondria Biogenesis and OXPHOS genes in heart failure including (Ndufs7, Ndufs8, Cycs, Sdhb, Sdhc, Uqcrb, Cyb5b, Ndufv1)
o See this article for more information https://doi.org/10.1038/s41467-017-00664-8).
o Please present results of study that you review for these genes to cover all points in clear way

 Write the methodological section in a clear logical way without number format in each section (about 4000 Words) (see file attached).

Reference
Liu, W., Ruiz-Velasco, A., Wang, S. et al. Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling. Nat Commun 8, 494 (2017). https://doi.org/10.1038/s41467-017-00664-8
Collins, H. E., Kane, M. S., Litovsky, S. H., Darley-Usmar, V. M., Young, M. E., Chatham, J. C., & Zhang, J. (2021). Mitochondrial Morphology and Mitophagy in Heart Diseases: Qualitative and Quantitative Analyses Using Transmission Electron Microscopy. Frontiers in aging, 2, 670267. https://doi.org/10.3389/fragi.2021.670267

Daghistani, H. M., Rajab, B. S., & Kitmitto, A. (2019). Three-dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets. British journal of pharmacology, 176(22), 4340–4359. https://doi.org/10.1111/bph.14499