Clearance of damaged mitochondria, or mitophagy, is a mechanism cells have evolved to maintain homeostasis and avoid deleterious effects of the dysfunctional organelle. We focus on PINK1/Parkin-dependent mitophagy, in which the kinase PINK1 is stabilized on the outer mitochondrial membrane and activates the E3 ubiquitin ligase, Parkin. Downstream of Parkin, mitophagy adaptors and regulators, such as the kinase TBK1, ensure that the damaged mitochondrion is engulfed in a double membrane phagophore. Mutations in PINK1, Parkin, TBK1 and other mitophagy effectors are linked to neurodegeneration and accompanying neuroinflammation. We performed functional assays using live and fixed cell microscopy and biochemical techniques to determine that several amyotrophic lateral sclerosis (ALS)-linked mutations in TBK1 impaired mitochondrial clearance, while other ALS-linked TBK1 mutations did not have an effect. We concluded that redundancies and crosstalk among mitophagic players ensure the clearance of mitochondria. However, complementing activities may not be as robust in specialized cell types, since expression of a TBK1 mutant that functioned in HeLa cells resulted in mitochondrial dysfunction and stalled mitophagy intermediates in neurons. Mitophagy proteins are also linked to neuroinflammation, in which patients and model animals exhibit upregulation of NF-ĸB transcripts, along with increased levels of toxic cytokines. The links between mitophagy and innate immune activation are not wholly clear. We used live and fixed cell microscopy, in vitro binding experiments, and quantitative polymerase chain reaction assays and found that damaged, ubiquitinated mitochondria recruit the NF-ĸB essential modulator (NEMO) in parallel to recruitment of mitophagy adaptors and the phagophore in HeLa. Subsequently, we found that inducing mitophagy led to the upregulation of NF-ĸB-induced inflammatory transcripts in a Parkin-dependent manner, suggesting a cell-autonomous pathway for mitophagy intermediates to stimulate innate immune signaling. NEMO was also recruited to damaged mitochondria in astrocytes. Future studies should assess the adverse or beneficial effects of this novel pathway, and whether NF-ĸB signaling initiated by mitophagy intermediates promotes non-cell-autonomous neuroinflammation.