| dc.description.abstract | Mitochondria are ubiquitous organelles placed at the nexus of several metabolic and signaling pathways essential for cell survival. Therefore, maintaining a healthy and functional organelle becomes paramount for the cell. The complex structural organization and the bi-genomic nature of the mitochondria pose a significant challenge in maintaining their homeostasis. In addition to the proteins encoded by the mitochondrial DNA (mtDNA), the mito-proteome primarily consists of nuclear-encoded proteins synthesized in the cytosol and subsequently translocated to the mitochondria. Thus, the biogenesis and functioning of the mitochondria are dependent on the efficient transport, folding, and localization of the nuclear-encoded proteins. Any disruptions in this chain of events can be detrimental to the mitochondria and, thereby, to the cell. As a result, several quality-control mechanisms have evolved that operate at multiple levels to abate any mitochondrial damage due to internal and external cellular stress.
Within the mitochondria, the import, folding, targeting, and degradation of proteins are regulated by the molecular chaperones. Among these, the mitochondrial Hsp70 (mtHsp70) is a crucial mediator of protein quality control. In conjunction with multiple co-chaperones, mtHsp70 performs two critical functions: the vectorial import of the nascent polypeptides into the mitochondria and their subsequent folding within the matrix. At the organellar level, a quality check is monitored by the segregation and degradation of superfluous or dysfunctional mitochondria via the process of mitophagy. This is achieved by the concerted action of AuTophaGy (ATG) related proteins and the dynamics of the mitochondrial network. Interestingly, studies reveal that increased mitophagy mitigates the effects of mtHsp70 mutations identified in patients with Parkinson’s disease, thus, suggesting an overlap between the quality control pathways. However, the details and implications of this interaction remain unexplored. Thus, in the current study, we have employed an array of genetic and biochemical techniques in the yeast model system to understand the overlap between the quality checkpoints and, further, to delineate the involvement of mtHsp70-mediated quality control in the progression of Congenital Sideroblastic Anemia (CSA).
We have explored how mtHsp70-mediated quality control engages and responds to the abrogation of mitophagy. Utilizing an unbiased genetic screen, we have identified mtHsp70 mutants that exhibit compromised growth without the mitophagy receptor, Atg32. This is accompanied by an alteration in the mitochondrial physiology, general autophagy, lipid homeostasis, and redox balance overall, resulting in a reduction in cellular lifespan. Our findings highlight the role of mtHsp70 in maintaining mitochondrial integrity under stress conditions and underscore the need for an overlap between the quality control pathways.
Further, we have investigated the role of mtHsp70 in the onset and progression of Congenital Sideroblastic Anemia (CSA), a hereditary blood disorder characterized by the accumulation of iron-laden mitochondria. Preliminary analyses of analogous mutations in the yeast mtHsp70 reveal perturbations in the mitochondrial network and functionality. Further, we observe mutations in mtHsp70 impair its import and chaperone activity resulting in a loss of function that manifests as the disease phenotypes observed in Congenital Sideroblastic Anemia.
The current study provides insights into the interaction between the various mitochondrial quality checkpoints and highlights the relevance of protein quality control in the context of Congenital Sideroblastic Anemia progression. | en_US |
