. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43. PubMed.

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  1. Mitochondrial Morphology as Hallmark in PINK1/Parkin-induced Pathology
    This excellent paper by Leo Pallanck and colleagues genetically manifests the interplay between PINK1 or parkin deficiency and changes in mitochondrial morphology. The authors were able to rescue PINK1 or parkin loss-of-function defects by genetic modifications that promote mitochondrial fission. Supporting these data, in Drosophila S2 cells the authors observed a fused mitochondrial phenotype after reduction of PINK1 or parkin expression by RNAi.

    Recent data from human HeLa cells showed that after RNAi-mediated knockdown of PINK1, a reduction in cristae density and in mitochondrial membrane potential was accompanied by changes in morphology that similarly occur in primary cells from patients with PINK1-associated PD after shift to low glucose conditions (1). These observations, as well as the fact that the phenotype could be rescued by increased expression of parkin, are very consistent with previous studies from Drosophila that reported fragmented cristae, reduced ATP content, and altered mitochondrial morphology in PINK1-deficient flies (2-4). These parallels point out the enormous potential of genetic studies in Drosophila to discover fundamental mechanisms that are relevant for human diseases.

    The human data diverge in one detail from what was here elucidated in the flies. In Drosophila, everything points toward a fission-promoting role of PINK1 and parkin, while in human cells truncation and fragmentation of mitochondria was described after downregulation of PINK1. In our view, this difference allows the hypothesis that the components involved in regulation of mitochondrial dynamics might not be direct targets of a PINK1/parkin signaling pathway, as this should lead to exact congruence of the PINK1-deficient mitochondrial morphology phenotypes. We rather suggest a stress-response mechanism that is induced by consequences of PINK1 deficiency. This may be mimicked in Drosophila by genetic modifications that favor mitochondrial fission.

    Fission of defective mitochondria is a protective mechanism that allows sequestration of damaged mitochondria and their elimination by mitophagy (5). The mechanism by which parkin exerts its rescuing activity during PINK1 loss-of-function was already suggested to be based on its neuroprotective potential. Recently, it was demonstrated that parkin can act through activation of NF-κB signaling to protect the cell against excitotoxicity and complex I inhibition (6). The antiapoptotic protein Bcl-2 as well was able to rescue PINK1 deficiency in Drosophila (3), which might also be mediated by a stress response mechanism. Bcl-2 is not restricted to mitochondria but also localizes to the ER, where it is involved in Ca2+ dynamics or in regulation of autophagy (7). Although by now several proteins are known to revert PINK1 phenotypes, the mechanisms by which they act could be based on general stress-protective attributes. Future studies, preferably in mammalian systems, are required to reveal the connection between PINK1 and its co-players.

    References:

    . Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007 Nov 7;27(45):12413-8. PubMed.

    . Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006 Jun 29;441(7097):1162-6. PubMed.

    . Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006 Jun 29;441(7097):1157-61. PubMed.

    . Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8. PubMed.

    . Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J. 2006 Aug 23;25(16):3900-11. PubMed.

    . Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci. 2007 Feb 21;27(8):1868-78. PubMed.

    . The daily job of night killers: alternative roles of the BCL-2 family in organelle physiology. Trends Cell Biol. 2008 Jan;18(1):38-44. PubMed.