DYNAMIC MITOCHONDRIA-ON-A-STRING (MOAS) FORMATION PROTECTS AGAINST STRESS IN ALZHEIMER’S DISEASE, HYPOXIA AND AGING

Abstract

Mitochondrial dysfunction and altered cellular energetics have been implicated in the etiology of Alzheimer's Disease (AD). Excessive mitochondrial division has been observed in cellular and animal models of familial AD (FAD), and in AD patients. Thus, understanding regional cellular responses to changes associated with disease progression, particularly regarding the relationship between mitochondrial energetics and the balance of mitochondrial fission and fusion, has the potential to elucidate basic mechanisms of disease while also suggesting targets of therapeutic opportunity. Using brain tissue from AD patients and animal models of familial FAD, processed using microwave enhanced fixation and staining, and serial block face electron microscopy and 3D volume reconstruction, we elucidated changes in mitochondrial morphology in the context of cellular and tissue architecture. We demonstrated that AD neuronal mitochondria display a highly exaggerated fission arrest phenotype that resembles ‘mitochondria-on-a-string’ (MOAS). MOAS formation was not associated with reduced levels of fission/fusion proteins or altered ability of Drp1 to translocate to mitochondria. The MOAS phenotype was mimicked in cultured neurons treated with the inhibitors of Drp1 GTPase activity, a\ in mice under hypoxic conditions, and in chronologically aged mice.