MITOCHONDRIAL FISSION AND NEURODEGENERATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nitric oxide (NO) plays a pivotal role in normal cell physiology. In brown fat tissue NO regulates mitochondrial biogenesis. In the central nervous system (CNS), NO functions as an important neurotransmitter, but when overproduced by excessive glutamate receptor activation, NO converts to peroxynitrite (ONOO-), a highly reactive, neurotoxic radical. NO-mediated neuronal injury is implicated in several neurodegenerative disorders, including stroke, Parkinsons disease, Alzheimers disease, Huntingtons disease, and ALS. NO/ONOO- inhibits mitochondrial respiration and ONOO- liberates Zn2+ from endogenous stores, which in turn triggers further mitochondrial injury. Besides these properties, NO/ONOO- activates signal transduction pathways of mitogen activated kinases, which can participate in neuronal demise. The mechanism underlying nitrosative stress-mediated neuronal cell death is not fully understood, but mitochondrial injury appears to be central. Thus a better understanding of the mechanism underlying mitochondrial injury during neurodegeneration is required. Electron microscopy and electron microscope tomography can help elucidate mitochondrial injury in the neurodegeneration models we are studying. Mitochondria are dynamic organelles, undergoing frequent fission and fusion. These opposing processes are choreographed by a conserved group of large GTPases. Their balanced activities dictate mitochondrial morphology, size, and number. Drp1, which is found in the cytoplasm and on mitochondria, has emerged as key mitochondrial fission factor. Upon activation by an unknown mechanism, Drp1 accumulates at mitochondria and preferentially localizes to future fission sites. Conversely, mitochondrial fusion is regulated by large GTPases, such as Mitofusin1 and 2 (Mfn1 and 2) and optic atrophy1 (OPA1). Mitochondrial fusion requires an intact mitochondrial membrane potential (DYm). Loss of either Mfn1, 2 or OPA1 results in mitochondrial fission and cellular dysfunction. Mitochondrial division is a normal physiological process; however, extensive mitochondrial division or fission can occur under patho-physiological conditions. Evidence has emerged indicating that mitochondrial fission plays an active part in apoptotic cell death. The work with Dr. Perkins at NCMIR principally involves the investigation of mitochondrial fission in cells and tissues.