Abstract
Cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF), are leading causes of mortality and morbidity globally. A major contributor to HF progression is mitochondrial dysfunction, resulting in oxidative stress, energy deficits, calcium dysregulation, and cardiomyocyte death. Despite the critical role of mitochondria in HF, there are currently no approved therapies that specifically target mitochondrial homeostasis. Emerging treatments provide indirect support through metabolic modulation, antioxidant therapy, and mitophagy regulation. Therefore, understanding the molecular mechanisms that prevent, or repair mitochondrial dysfunction is essential for developing novel therapies, including mitochondrial quality control enhancers, mitophagy inducers, and gene-based approaches.</span></p><p><span style="color: rgb(0, 0, 0);">The mitochondrial unfolded protein response (UPRmt), a protective stress response activated by mitochondrial protein damage, mito-nuclear imbalance, or depolarisation, holds promise for cardioprotection. However, the role of UPRmt in the heart remains poorly defined. My thesis investigates the pathways and molecular mechanisms governing UPRmt in stressed cardiomyocytes.</span></p><p><span style="color: rgb(0, 0, 0);">The first part of this study identifies upstream signals leading to UPRmt activation. Our findings reveal that under mitochondrial stress, integrated stress response (ISR) is activated upstream, involving the formation of stress granules (SGs), PERK activation and autophosphorylation, eIF2α phosphorylation, and preferential activation of transcription factors ATF4, ATF5, and CHOP. This cascade alleviates stress and initiates UPRmt, maintaining cellular homeostasis.</span></p><p><span style="color: rgb(0, 0, 0);">The second part explores ATF5’s interacting partners, particularly NRF2, which forms a complex with its endogenous inhibitor KEAP1 and mitochondrial phosphatase PGAM5 on the mitochondrial membrane. During stress, PGAM5 levels decrease, releasing NRF2 from the complex to translocate to the nucleus and enhance subset of UPRmt marker expression, improving mitochondrial respiration. </span></p><p><span style="color: rgb(0, 0, 0);">Finally, we investigated downstream pathways of ATF5, one of the key mediators of UPRmt. These include pathways related to cellular metabolism, cAMP, calcium signalling, JAK-STAT and PI3K-Akt signalling, gene expression, mitochondrial organisation, oxidative stress, and apoptosis. Together, these findings provide novel mechanistic insights into UPRmt regulation and highlight therapeutic targets for mitigating mitochondrial dysfunction in HF.