Browsing by Author "Mukherjee, Piyali"

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    Exploring the role of NAD metabolism in response to mitochondrial respiratory chain inhibition
    Mukherjee, Piyali
    Mitochondrial Complex I deficiency has been reported in several diseases and strongly linked to patients with Parkinson ’s disease. However, there is poor mechanistic understanding of the pathways involved and no treatment regimen is currently available for mitochondrial complex I deficiency disorders. Rotenone is a potent inhibitor of mitochondrial ETC complex I. Several studies have indicated that rotenone-mediated cell death is associated with mitochondrial depolarization, DNA damage, and ROS generation that corroborates with similar observations in other mitochondrial complex I deficiency disorders but there lacks a comprehensive understanding of the cell death network induced by the deregulation of these pathways. Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that bridges mitochondrial energy production with metabolism. However, how NAD+ modulates cellular homeostasis in response to mitochondrial respiratory chain inhibition has not been comprehensively explored so far. This study focuses on understanding the events that lead to NAD+-dependent cell death following mitochondrial complex I inhibition. Our study revealed that early loss of endogenous NAD+ due to hyperactivation of PARP1 in the presence of rotenone may act as a ‘biological trigger’ of NADase Sarm1 activation in the presence of mitochondrial complex I inhibitor rotenone. This study demonstrated, replenishing NAD+ levels by PARP1 inhibitor, PJ34/Olaparib restored mitochondrial complex I activity, and early loss of NAD+, thereby preventing the activation of Sarm1. This conservation of NAD+ via PARP inhibition stimulated mitophagy and removal of damaged mitochondria, thereby preventing sustained ROS production. These cellular data were further validated in Drosophila melanogaster (w1118) where a significant reduction in rotenone-induced loss of locomotor abilities, reduced inflammatory response, restoration of dopaminergic neuronal loss, and reduced dSarm expression was observed in flies following PARP inhibition via the clinical inhibitor, Olaparib. Collectively, these observations not only uncover a novel regulation of cell death via endogenous NAD+ levels but also point towards an important understanding of how PARP inhibitors could be repurposed in the treatment of mitochondrial complex I deficiency disorders.
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    Understanding the Regulation of Mitochondrial Homeostasis by SARMI and its role in Neurodegeneration
    Mukherjee, Piyali
    With the increase in life expectancy neurodegenerative diseases like Alzheimer s disease (AD) and Parkinson s disease (PD) are on the rise. While neurodegeneration has been studied in the context of various pathological conditions, not much is known on the molecular mechanisms that cause/regulate axonal retraction during aging. Identification of key targets that delay the process of neuronal death before they reach the point of no return may enhance their longevity and prevent subsequent disease pathology. SARM1 (Sterile alpha and TIR motif-containing 1 protein) is a key molecule that plays a pivotal role in axonal death. To study the role of endogenous SARM 1 we established a cellular model of neurodegeneration in SH-SY5Y cells by treatment with the mitochondrial complex I inhibitor rotenone. We showed that rotenone induced neuronal death through SARM1 activation that was accompanied by increased inflammation, deregulation of electron transport chain (ETC) complex genes and defective autophagy. To study age-associated neurodegeneration, we established a drosophila model of aging for the study of age-dependent vulnerability to rotenone, a pesticide that has been implicated in sporadic cases of PD. Our results showed that age plays a major role in the increased susceptibility to rotenone that is accompanied by decreased lifespan, severe locomotor deficits, and loss of dopaminergic neurons. Rotenone exposure results in the SARM1 induction that is accompanied by an increased inflammatory response and independent of ROS generation. Thus, this study aims to provide a detailed mechanistic insight into the regulation of neuronal homeostasis by SARM1 and its implication in age-associated neurodegeneration.