Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, but currently there is no cure for PD. Mutations in PINK1 and parkin cause a recessive form of early onset familial PD. PINK1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial morphology and quality, which underscores that mitochondrial dysfunction contributes to PD progression. Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fission and fusion. PINK1 functions as a mitochondria-localized Serine/Threonine kinase and Parkin as a cytosolic E3 ligase to target the fusion GTPase Mfn for degradation, thus inhibiting mitochondrial fusion. Moreover, PINK1 and Parkin maintain mitochondrial quality by promoting autophagy of dysfunctional mitochondria, a process named “mitophagy”. Discovery of the PINK1-parkin pathway provides an entry point to isolate other genes and compounds that suppress the pathological phenotypes due to lack of PINK1/parkin, which hold great therapeutic potential for development of drugs to treat PD and/or alleviate its symptoms. In this context, we previously found that expression of the pro-fission GTPase Drp1 or inhibition of Mfn suppresses tissue damage and mitochondrial dysfunction in PINK1/parkin mutant Drosophila. In my dissertation research, I combined our Drosophila PINK1/parkin loss-of-function PD model with mammalian cell-based mitochondrial morphology and mitophagy assays, and found that expression of the evolutionarily conserved gene clueless also suppresses PINK1/parkin null mutant phenotypes in Drosophila, and that Drp1 is a critical target of clueless (Drosophila homolog)/cluH (human homolog). Overexpression of drp1 rescues adult lethality, tissue damage, cell death and mitochondrial dysfunction in clueless null mutant Drosophila. In addition, loss of clueless/cluH results in mitochondrial elongation, while clueless/cluH overexpression results in mitochondrial fragmentation in Drosophila and mammalian cells. Clueless/CluH binds Drp1 and promotes its recruitment to mitochondria, providing a mechanistic basis for the above phenotypes. Furthermore, I demonstrated that regulation of Drp1 by cluH is mediated by direct protein interactions between CluH and Drp1 receptors MiD49 and Mff in mammalian cells, and that cluH positively regulates MiD49 and Mff protein levels through posttranscriptional mechanism. Finally, loss of cluH in HeLa cells results in impaired mitophagy due to decreased mitochondrial recruitment of Drp1, and expression of the constitutive mitochondria-localized Drp1S637A rescues the mitophagy defects in cluH KO cells. Together these observations provide insights into how clueless/cluH regulates mitochondrial morphology and quality, and compensates for loss of PINK1/parkin through promoting mitochondrial fission.