. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS One. 2009;4(5):e5701. PubMed.


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  1. The key difference between this study and the previous Drosophila studies is that a transformed neuroblastoma cell line is used here, whereas previous studies looked at postmitotic neurons and muscle in an in-vivo setting using Pink1-null mutant animals. It is known that mitochondria in proliferating cells and differentiated cells are very different, both in terms of morphology and function. This may account for the different conclusions from these studies. Future studies using postmitotic neurons, preferably dopaminergic neurons from Pink1 knockout animals, will be required to make fair comparisons between the studies.

    View all comments by Bingwei Lu
  2. PINK1: Mitochondria bioenergetics dysfunction or deficient mitochondria dynamics? This question has raised some controversy in the Parkinson disease (PD) field in recent years. This matter is elegantly tackled in this paper from Sandebring and co-workers, where the authors attempt to address the underlying mechanism by which PINK1 influences mitochondrial morphology. In sum, they propose a mechanism where loss of PINK1 function causes decreased mitochondrial membrane potential (as has been previously reported by others), altering Ca2+ homeostasis, leading to the dephosphorylation of DRP1.

    These findings link the mitochondrial functional deficits with secondary mitochondria morphology alterations. Moreover, their findings are in complete agreement with our own work, recently published in EMBO Molecular Medicine [1], where we also claim that mitochondrial dysfunction is upstream of mitochondrial morphological defects observed in PINK1-deficient models. In our work, we also observed a decrease in mitochondrial membrane potential in two PINK1-deficient animal models (mouse and Drosophila).

    Furthermore, we have pinpointed this deficit to reduced Complex I activity. The reduced Complex I activity can be rescued by the human PINK1 wild-type form, but not by the familial PD mutations found in PINK1. Additionally, we also observe a synaptic deficit at the level of the neuromuscular junction of Drosophila larvae, which can be rescued with forward-fill of ATP, which strongly implicates an energy limitation.

    Sandebring et al. are careful to state that their proposal does not imply that PINK1 directly controls the mitochondrial membrane potential [1]. We, on the other hand, believe that the reduced activity of Complex I, which is known to cause reduced mitochondrial membrane potential, is due to the absence of PINK1. Whether a sub-unit of Complex I is a direct or indirect substrate for PINK1 is something that still needs to be addressed. At present, our efforts are devoted to identifying this promiscuous substrate that is leading to a mitochondrial bioenergetics dysfunction. Until we know this substrate, we are gratified that additional research groups corroborate our working hypothesis. Hopefully the “flurry” around PINK1, as also discussed by Anne Murphy in a Closeup of EMBO Molecular Medicine Journal [2], will strengthen the fact that these two aspects of mitochondrial morphology and bioenergetics are intimately associated. In future studies, one should take into consideration that mitochondria morphology alterations are downstream effects of a more complex deficiency occurring at the level of mitochondria function.


    . Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med. 2009 May;1(2):99-111. PubMed.

    . In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease. EMBO Mol Med. 2009 May;1(2):81-4. PubMed.

  3. Accumulating evidence indicates that mitochondrial dysfunction is a key factor in the pathophysiology of Parkinson disease (PD). Inhibitors of complex I of the electron transport chain, such as MPTP and rotenone, can induce parkinsonism, and a decreased activity of complex I has indeed been detected in the substantia nigra of patients suffering from PD. Remarkably, the identification of genes associated with familial PD confirmed the crucial role of mitochondria for the integrity of dopaminergic neurons. One of the genes associated with autosomal-recessive PD encodes a bona fide mitochondrial protein, PINK1, a serine/threonine kinase that can protect cells against mitochondrial toxins.

    In Drosophila melanogaster, loss of PINK1 function causes apoptotic flight muscle degeneration and defective spermatogenesis, and mitochondrial pathology is the earliest manifestation of these phenotypes (Clark et al., 2006; Park et al., 2006; Yang et al., 2006). PINK1 deficiency in flies can be rescued by increasing mitochondrial fission or decreasing fusion, leading to the conclusion that PINK1 promotes mitochondrial fission (Deng et al., 2008; Park et al., 2009; Poole et al., 2008; Yang et al., 2008). In contrast, when PINK1 is downregulated in cultured mammalian cells, an increase in mitochondrial fragmentation has been observed (Dagda et al., 2009; Exner et al., 2007; Weihofen et al., 2009).

    In the present study from Mark Cookson's group, this discrepancy was elegantly addressed. By using human neuroblastoma cells stably expressing wild-type PINK1, pathogenic PINK1 mutants or PINK1 shRNA, Sandebring and colleagues were able to demonstrate that increased expression of PINK1 can prevent mitochondrial fragmentation induced by rotenone treatment in a kinase-dependent fashion. In PINK1-deficient cells an increase in mitochondrial fragmentation was observed, and rotenone treatment added to that effect.

    Downregulation of Drp1, a GTPase promoting mitochondrial fission, significantly prevented mitochondrial fragmentation in PINK1-deficient cells. The activity of Drp1 is regulated by post-translational modifications; therefore, the authors analyzed whether in PINK1-deficient cells the phosphorylation status of Drp1 might be altered. They observed that loss of PINK1 function is associated with a decrease in phospho-Drp1 levels and an increase in Drp1 GTPase activity. Calcineurin is a phosphatase known to dephosphorylate Drp1 at S637; therefore, Sandebring and colleagues tested PINK1-deficient cells for expression levels and activity of calcineurin. They found that calcineurin activity was significantly increased in PINK1 knockdown cells, while expression levels were not affected. Interestingly, the calcineurin inhibitor FK506 ws able to rescue mitochondrial fragmentation caused by loss of PINK1 function.

    This study clearly shows that PINK1 silencing in human cells promotes mitochondrial fragmentation, which is dependent on Drp1 and involves calcineurin-mediated dephosphorylation of Drp1. How does this fit with what has been reported for PINK1-deficient flies? The most plausible explanation is that the phenotype observed in adult flies is influenced by compensatory effects. The accumulation of damaged mitochondria in PINK1-deficient flies might be a stimulus to activate fusion in an attempt to dilute these dysfunctional mitochondria (McBride, 2008). In tissues with high energy demand, such as flight muscles or spermatides, this strategy might not be efficient to remove damaged mitochondria. Thus, activation of mitochondrial fission might be beneficial, as it favors clearance of dysfunctional mitochondria by autophagy (Twig et al., 2008). All in all, the studies in mammalian cells and flies clearly demonstrate that PINK1 has an impact on mitochondrial function and integrity. It will now be important to unravel the underlying mechanism and to elaborate on the functional interaction between PINK1 and parkin.

    View all comments by Konstanze Winklhofer

This paper appears in the following:


  1. Form or Function: How Does Pink1 Deficiency Mar Mitochondria?