Mitochondria are semi-autonomous organelles that contain their own genetic machinery. As such, they operate under the dual genetic controls of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial genetics differs markedly from mendelian genetics, because first, mitochondria are inherited exclusively from the mother, and second, there are hundreds or thousands of mitochondria (and mtDNAs) per cell. Biochemically, the most relevant aspect of mitochondrial function is the production of oxidative energy via the respiratory chain and oxidative phosphorylation. There are maternally-inherited, mendelian-inherited, sporadic, and even environmentally-induced mitochondrial disorders, most of which are fatal. We are studying the molecular basis of a number of these diseases, often using cytoplasmic hybrids, or "cybrids," that contain known proportions of mutant or wild-type mtDNAs in clonal cell lines that have no contaminating mtDNA background. We have also begun a project on treating mtDNA-based disease using pharmacological approaches aimed at "shifting heteroplasmy" in order to restore respiratory function in patient-derived cells. Most recently we have become interested in the pathogenesis of Alzheimer disease, and have discovered that presenilin-1, presenilin-2, and gamma-secretase activity itself, are located predominantly in a specialized subcompartment of the ER that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). We have found that cells from AD patients have massively increased ER-mitochondrial communication, which may help explain many of the seemingly unrelated features of the disease. We believe that this hyperconnectivity plays a fundamental role in the pathogenesis of AD, with implications for both diagnosis and treatment of this devastating disorder.