ABSTRACT Organelle contact and communication are important for the health of cells. Alteration of the relationship between organelles, such as endoplasmic reticulum (ER) and mitochondria, influences the transfer of ions, lipids, and proteins, impacts inter-organelle dynamics and is associated with diseases. Our hypothesis is that defects in mitochondria and ER contact result in decreased mitochondrial clearance by autophagy (mitophagy), increased cell stress, and inflammation that underlie age-associated and progressive movement disorders. In support of our hypothesis, we discovered the previously uncharacterized lipid transfer protein VPS13D as a regulator of mitochondrial size and mitophagy, and showed that VPS13D influences ER and mitochondria contact. Importantly, these phenotypes are conserved between diverse taxa, including fruit flies and humans. In addition, we have recently discovered that VPS13D mutant cells possess elevated markers of stress and inflammation. Loss of VPS13D results in progressive and age-associated human disease, including spastic ataxia and paraplegia. Significantly, our recently developed VPS13D conditional knockout mutant mouse model exhibits phenotypes that are consistent with observations in patients and patient-derived cells. Our goal is to characterize the role of VPS13D mutation-associated mitochondria and ER contact in fibroblasts that were derived from patients and our recently developed knockout mouse model. Here we propose to: (1) determine if altered organelle contact in VPS13D patient-derived fibroblasts influences age-associated cell defects in mitophagy, stress and inflammation, (2) examine VPS13D conditional knockout mutant mice for defects in organelle contact and neurological phenotypes, and (3) investigate VPS13D pathway genes for suppression of disease phenotypes. The association of altered organelle contact, autophagy, stress, and inflammation with age-associated disorders illustrates the importance of investigating the relationship between these processes in cell and animal health.