Mitochondria: the next (neurode)generation

Abstract

Adult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders.

Fig. 1. Mitochondrial interactions in neurodegenerative diseases

Proteins associated with mutations causing neurodegenerative disorders are in colored ovals (colored according to the key), and are associated with four broad mitochondrial functions (black rectangles). White ovals indicate selected relevant mitochondrial proteins not currently associated with neurodegenerative disease. In general, only pathogenic proteins discussed in the text are shown; note that some proteins not discussed here are also associated with mitochondria, either directly or indirectly (Table 3); HTRA2/OMI and HSPD1, associated with PD and HSP, respectively, are included in the figure for completeness, but were not discussed in the text. Proteins that “touch” each other indicate a physical or genetic interaction. For simplicity, the figure does not show all interactions, or shows some interactions that occur only in some tissues or at specific times, or both; conversely, some interactions are speculative, based on extrapolations from the literature. See text for details. IMS, intermembrane space; MAM, mitochondria-associated ER membranes; MIM, mitochondrial inner membrane; MOM, mitochondrial outer membrane; m, mutant; Δ-mtDNAs, large-scale partial deletions of mtDNA.