Rahme Nese Safakli
About
My research project
Identifying the mechanisms that define the mitochondrial unfolded protein response in the stressed heartCardiovascular diseases, particularly acute myocardial infarction (MI) and chronic heart failure (HF), cause a large number of deaths and have a significant impact on quality of life. Mitochondrial dysfunction is a key aspect of heart failure, as it contributes to oxidative stress, energy deficits, calcium dysregulation, and cardiomyocyte mortality, and is thus viewed as a prospective therapeutic target. There are currently no interventions that explicitly improve or maintain mitochondrial homeostasis in failing heart. In order to develop novel therapies for heart failure, we must uncover new molecular targets that work to prevent and/or restore mitochondrial defects. The mitochondrial unfolded protein response (UPRmt) is a cellular stress response that is activated in response to damage to mitochondrial proteins, an imbalance between the mitochondrial and nuclear proteome (mitonuclear imbalance), or other stresses, such as mitochondrial depolarization. Our knowledge of the molecular processes behind the UPRmt-mediated cardioprotection is, however, limited. The aim of this study is to identify and characterise the mechanisms that define the mitochondrial unfolded protein response in the stressed heart.
Supervisors
Cardiovascular diseases, particularly acute myocardial infarction (MI) and chronic heart failure (HF), cause a large number of deaths and have a significant impact on quality of life. Mitochondrial dysfunction is a key aspect of heart failure, as it contributes to oxidative stress, energy deficits, calcium dysregulation, and cardiomyocyte mortality, and is thus viewed as a prospective therapeutic target. There are currently no interventions that explicitly improve or maintain mitochondrial homeostasis in failing heart. In order to develop novel therapies for heart failure, we must uncover new molecular targets that work to prevent and/or restore mitochondrial defects. The mitochondrial unfolded protein response (UPRmt) is a cellular stress response that is activated in response to damage to mitochondrial proteins, an imbalance between the mitochondrial and nuclear proteome (mitonuclear imbalance), or other stresses, such as mitochondrial depolarization. Our knowledge of the molecular processes behind the UPRmt-mediated cardioprotection is, however, limited. The aim of this study is to identify and characterise the mechanisms that define the mitochondrial unfolded protein response in the stressed heart.
Publications
The mitochondrial unfolded protein response (UPRmt) is a conserved signalling pathway that initiates a specific transcriptional programme to maintain mitochondrial and cellular homeostasis under stress. Previous studies have demonstrated that UPRmt activation has protective effects in the pressure-overloaded human heart, suggesting that robust UPRmt stimulation could serve as an intervention strategy for cardiovascular diseases. However, the precise mechanisms of UPRmt regulation remain unclear. In this study, we present evidence that the NRF2 transcription factor is involved in UPRmt activation in cardiomyocytes during conditions of mitochondrial stress. Silencing NRF2 partially reduces UPRmt activation, highlighting its essential role in this pathway. However, constitutive activation of NRF2 via inhibition of its cytosolic regulator KEAP1 does not increase levels of UPRmt activation markers, suggesting an alternative regulatory mechanism independent of the canonical KEAP1-NRF2 axis. Further analysis revealed that NRF2 likely affects UPRmt activation through its interaction with PGAM5 at the mitochondrial membrane. Disruption of PGAM5 in cardiomyocytes subjected to mitochondrial stress reduces the interaction between PGAM5 and NRF2, enhancing nuclear translocation of NRF2 and significantly upregulating the UPRmt in an NRF2-dependent manner. This NRF2-regulated UPRmt amplification improves mitochondrial respiration, reflecting an enhanced capacity for cardiomyocytes to meet elevated energetic demands during mitochondrial stress. Our findings highlight the therapeutic potential of targeting the NRF2-PGAM5-KEAP1 signalling complex to amplify the UPRmt in cardiomyocytes for cardiovascular and other diseases associated with mitochondrial dysfunction. Future studies should aim to elucidate the mechanisms via which NRF2 enhances the protective effects of UPRmt, thereby contributing to more targeted therapeutic approaches.
To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2a phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that may contribute to restoring mitochondrial functions under stressful conditions.