If so, how can we reconcile a role for mitochondria

in these disorders, given the large literature implicating energy metabolism? Perhaps the recent shift in emphasis regarding the role of mitochondria in neurodegenerative disorders reflects a better appreciation of the relationship between cause and effect in these diseases, namely, that impaired OxPhos is not the cause of neurodegeneration, but is one result of other underlying mitochondrial problems. Furthermore, we recognize that while changes in mitochondrial function do not necessarily have to affect MDV3100 molecular weight bioenergetic output, the fact remains that if, for example, mitodynamics are perturbed, the absolute production and local delivery Cabozantinib supplier of ATP will be reduced, and that at

some point in the disease process bioenergetic failure will occur, probably delivering the coup de grâce. We have entered a new era of mitochondrial biology, one in which the focus is no longer solely on bioenergetics per se but on mitochondria as an integrated subcellular system (Figure 1). Under this rubric, a central theme that has emerged is one of altered mitochondrial dynamics. While important advances have been made in this area in a relatively short period of time, some key outstanding questions still remain to be addressed. For example, if diseases such as AD, ALS, and PD are due to errors in mitochondrial quality control overseen by a suite of ubiquitous housekeeping proteins, why do these diseases display a predilection for specific subpopulations of neurons? To almost belabor the obvious, the simple answer is that some specific neurons may be more vulnerable most to the pathological process than others; clearly, such a differential neuronal susceptibility will only reveal itself if the defect in question is mild, as would be expected for an adult-onset neurodegenerative disorder. Based on this premise, let us use PD to illustrate a putative pathogenic scenario, by comparing two subpopulations of dopaminergic neurons from the ventral midbrain that are affected differentially in the disease, namely those in the substantia

nigra (severely affected) and those in the ventral tegmental area (mildly effected) (Dauer and Przedborski, 2003). One compelling difference between these two groups of neurons is that recruitment of L-type calcium channels during normal autonomous pacemaking is associated with a high ROS signal in dopaminergic neurons of the substantia nigra, but not those of the ventral tegmental area (Guzman et al., 2010). Thus, one could speculate that the former region accumulates a much higher burden of ROS-related mtDNA mutations than the latter, a view that is, in fact, supported by the observation that dopaminergic neurons in the substantia nigra of both aged normal subjects (Kraytsberg et al., 2006) and PD patients (Bender et al., 2006) contain more mtDNA deletions than do those from controls.