. 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. 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.

    References:

    . 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.

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