Year: 2021
Type: dissertation
Abstract: NOD-like receptors are a family of intracellular detectors of microbial and danger signals, that perform a range of functions regarding innate immunity. One member of this family, NLRX1, is the only NOD-like receptor to be localized to mitochondria. The findings in this thesis elucidate the true function of NLRX1, which is to facilitate mitophagy in response to mitochondrial stress. In situations where mitochondria are damaged beyond repair, they are engulfed and degraded through the process of mitophagy. Mitophagic clearance recycles molecular building blocks and prevents the accumulation of damaged mitochondria that can release dangerous molecules like reactive oxygen species and mitochondrial DNA and trigger apoptosis when not degraded. In Chapter 2, I investigate the functional interaction of NLRX1 with SARM1. Not only has SARM1 been implicated in apoptosis as a pro-death player, but it is also essential for the process of axonal degeneration. We show that NLRX1 modulates apoptosis through SARM1 and confirm the putative interaction and show that it is dependent on the leucine-rich repeat domain of NLRX1. We then demonstrate that NLRX1 is not involved in the axonal degeneration process that SARM1 oversees following axotomy, NGF withdrawal or vinblastine treatment. In Chapter 3, we identify a cytosolic pool of NLRX1 that is retained and stabilized outside of the mitochondria following mitochondrial stress. We then demonstrate that through interaction with an endoplasmic reticulum protein, RRBP1, NLRX1 facilitates mitophagy following depolarization and mitochondrial protein import stress. Mitophagy following import stress was not operating through the canonical pathway of PINK1-Parkin mitophagy, suggesting that the NLRX1-RRBP1 axis is independent of the canonical route. We then used exhaustive exercise to induce physiological mitophagy in mice and found that NLRX1-deficient animals had a reduced endurance capacity, accompanied by a reduction in mitophagy in the gastrocnemius muscle. Taken together, we propose that NLRX1 facilitates physiologically relevant mitophagy through RRBP1 to preserve mitochondrial and cellular homeostasis. This novel axis could be promoted in a therapeutic setting to prevent the buildup of toxic mitochondria that is commonly seen in many neurodegenerative diseases.
Source: TSpace (University of Toronto)
Author: Killackey, Samuel
Institution: University of Toronto
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133096766