Mitochondria are central regulators of multiple critical cellular processes. Mitochondrial dysfunction, therefore, severely compromises cellular integrity. Mutations in mitochondrial DNA (mtDNA), dysfunction of the electron transport chain, excessive oxidative stress, imbalance in mitochondrial turnover, disruption of the fusion/ fission machinery, impaired trafficking, and defective mitochondrial proteostasis are widely implicated in disease pathology and organismal aging. However, less is understood about the interdependence of these different aspects of mitochondrial biology. For example, it is unclear how mtDNA depletion impacts mitochondrial trafficking. Similarly, the effect of increased oxidative stress on mitochondrial proteostasis is unknown. In this dissertation, I have investigated the regulation of mitochondrial dynamics in the context of mtDNA disorders, and the regulation of the mitochondrial proteostasis machinery in the context of aging and healthy lifespan.In Chapter 2, I will discuss the implications of blocking mtDNA replication on mitochondrial biogenesis, distribution and trafficking. We demonstrate that mtDNA depletion results in an upregulation of mitochondrial biogenesis and increased bidirectional axonal transport in Drosophila. Transport of other axonal cargoes is largely unaffected, indicating a specific regulation of mitochondrial axonal transport. We interpret these results in the context of an SOS response that is activated to replenish the presynaptic terminal with functional mitochondria. These data uncover a novel contributory mechanism in distal neuropathy, often associated with mtDNA disorders. In Chapter 3, I will present evidence that a mitochondrial chaperone TRAP1 is involved in regulating resistance to oxidative stress in Drosophila. Interestingly, there is only a marginal influence on lifespan, challenging the conventional belief that oxidative stress resistance is causally associated with longevity. Remarkably, dosage modulation of this mitochondrial chaperone has dramatic effects on the fitness and health of aging flies. This role of TRAP1 is mediated at least partially through the activation of the mitochondrial unfolded protein response. We discuss these results in the context of organismal aging and healthspan.Taken together, this dissertation has uncovered novel mechanisms by which mitochondria deal with at least two different stressors, mtDNA depletion and oxidative stress. In Chapter 4, I will discuss my findings in the perspective of mitochondrial quality control and its larger implications in human diseases and health. I will also briefly explore unanswered questions that arise from my work and the directions of future research and avenues open.
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