Mitochondrial signaling and neurodegeneration

The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic inflammation, and protein aggregates, remain unclear. Emerging evidence demonstrates that mitochondria are not only power- generating organelles, but also engage in signaling at multiple levels. During the bioenergetic decline associated with aging, dysfunctional mitochondria generate signals of stress (SOS) that can trigger and/or amplify neurodegenerative processes. In this chapter, we describe emerging mechanisms for mitochondrial signaling at four different levels. Mitochondria communicate (1) with each other via fusion and specialized inter-mitochondrial junctions, (2) with cytoplasmic components via posttranslational modifications that shift signaling pathways and promote protein aggregation, (3) with the nucleus to regulate epigenetic modifications and gene expression, and (4) with the systemic environment where they alter neuroendocrine and inflammatory processes that impact neuronal function. The relevance of mitochondrial signaling to neurodegeneration is discussed.