Research Projects

Programmed cell death (PCD) is an indispensable process for organism development, and its dysregulation is directly implicated in various disease pathologies. PCD is majorly regulated by mitochondria in the cell, which is orchestrated by multiple proteins in their distinct compartments. While some inner mitochondrial membrane proteins are involved in protein import activity, emerging evidence suggests that these import machinery can exhibit non-canonical functions under altered cellular conditions. The TIM22 complex is essential for inserting transmembrane proteins into the inner membrane of mitochondria. Interestingly, emerging studies suggest that this complex has a secondary function in cell death, as several cytotoxic factors utilize it to enter the mitochondria to mediate apoptosis. Apoptosis-inducing factor (AIF) is one of the essential factors in apoptosis, though its exact role in human diseases like neurodegeneration and mitochondriopathy is still enigmatic. The AIF protein is highly conserved across species, from humans to yeast. Recent reports highlight that Nde1, a yeast AIF homolog, exhibits induction of apoptosis in cells with compromised respiration, with a non-catalytically active form accumulating in the stressed cells to trigger cell death. Our preliminary findings indicate that the TIM22 complex (inner mitochondrial transport machinery) is involved with the mitochondrial distribution of Nde1. Furthermore, most of the temperature-sensitive mutants from the TIM22 complex (core and subunits) in yeast showed increased resistance to Nde1-mediated toxicity. This suggests that there is a functional crosstalk between Nde1/AIF in regulating mitochondrial functions and the interplay between the cell death pathways. Thus, the current proposal aims at understanding the novel pathway connecting the inner membrane transport machinery (TIM22 complex) with the AIF functions utilizing the Saccharomyces cerevisiae and mammalian system. The research investigation will provide valuable new insights into mitochondrial-linked disease pathogenicity, including neurodegenerative diseases and cancer.