PINK1 in mitochondrial function.

R are, inherited mutations causing familial forms of Parkinson’s disease (PD) have provided much insight into some of the molecular mechanisms that underlie both the genetic and sporadic forms of the disease. The role of mitochondria in sporadic PD has been debated for a little over 20 years, since the identification of complex I deficiency in the substantia nigra pars compacta (SNpc) (1). However, it was the identification of loss-of-function recessive mutations in the PINK1 gene, encoding a mitochondrial, putative protein kinase, that reignited interest in the pathophysiology of mitochondria and their potential role in parkinsonism (PARK6) (2). In Drosophila models of PINK1, it has been shown that PINK1 and parkin (the PARK2 locus) (3) act, at least in part, in a common pathway. These studies strongly suggested a role for PINK1 in normal mitochondrial function and implied that parkin was downstream of PINK1. Nevertheless, the role of PINK1 in mammalian mitochondrial function remained unclear. The role of DJ-1 a third recessive parkinsonism locus (PARK7) (4) is also likely to relate to mitochondrial function (5), although whether it too maps to the same pathway as PINK and parkin is not yet clear. In any event, these genetic data clearly show an important role for the mitochondrion in the recessive parkinsonisms, although the extent to which these findings will be relevant to sporadic PD remains unclear (1, 6). The report by Gautier et al. (7) in this issue of PNAS focuses on mitochondrial functional defects in mice lacking expression of PINK1 (PINK1 / mice). They show that mitochondrial respiration is impaired in the striatum of the PINK1 / mice at 3–4 months. The next step will be to confirm these observations in the SNpc of the PINK1 / mice. Furthermore, respiratory-chain dysfunction has been found in tissues outside of the brain of PD patients. In particular, data on skeletal muscles are still difficult to interpret (8). It will therefore be interesting to extend the present study to other PINK1 / tissues. A selective decrement in mitochondrial complex I in terms of the involvement of other components of the respiratory chain is generally agreed by the scientific community to be associated with sporadic PD. In the present study (7), defects in complex I and also in complexes II–IV were observed in the striatum of the PINK1 / mice. These latter defects are relatively novel in a PD model. Most previous studies have demonstrated only a complex I deficiency, although some have also reported defects in complexes II–IV in PD patients (8). Future investigations will clarify whether the association of complex I with PD was effectively selective or whether other complex deficiencies could also play an important role in the pathogenesis of the disease. Even though the respiratory-chain dysfunction has been widely described in PD models, it will be important to elucidate the mechanism of impaired respiration in models without the use of complex I toxins. In addition, PINK1 / mice (7) display reduced aconitase activity. It has been shown that aconitase activity was reduced in rat cerebellar granule neurons upon MPP treatment (9) and in the brain of DJ-1 / mice (10). Therefore, it might be interesting to investigate whether mitochondrial aconitase may impart susceptibility to PD. In contrast to mitochondria derived from indirect f light muscles in dPINK1 / f lies (11–13), no major structural defect was observed in mitochondria of PINK1 / mice. Nevertheless, the number of larger mitochondria was increased in the striatum of the mice. This is an interesting observation because PINK1 has been suggested to promote mitochondrial fission and to regulate mitochondrial morphology in Drosophila and mammalian models (11– 16). Mitochondrial fission in mammalian cells is mediated by DRP1, along with other proteins such as the mitochondrial protein FIS1. Notably, pharmacological inhibition of respiratory-chain complex I alters the organization of the mitochondrial network. It is widely accepted that an imbalance between fusion and fission activities is causative for many pathophysiological conditions. Furthermore, mutations in genes regulating mitochondrial morphology are causally linked to