. 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.

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  1. We appreciate the comments of Dr. Pallanck on our work, but would like to add some additional information that will allow the reader to put this criticism in perspective. First, it should be noted that no molecular mechanism has been provided for the putative role of Pink1 in mitochondrial fission, and that our work provides an experimentally well-supported alternative mechanism to explain the available observations. We refer to our paper for further discussion.

    More importantly, some additional background on the experiments of Choi et al., as cited by Dr. Pallanck, will shed more light on the interpretation of these data. The animal toxin models that use mitochondrial Complex I inhibitors, such as MPTP and rotenone, to induce PD-like symptoms are widely used to study PD. Studies performed by researchers led by Zhengui Xia and Richard Palmiter have reported that upon deletion of an assembly factor of Complex I, Ndufs4, dopaminergic neurons remain sensitive to well-established Complex I mitochondrial inhibitors, arguing that dopaminergic neuron loss is not due to Complex I inhibition (Choi et al., 2008). However, the original report by Palmiter and colleagues (Kruse et al., 2008) shows clearly that tissue from Ndufs4-/- mice retains approximately 50 percent of respiration driven by Complex I substrates. This is in complete accordance with the 50 percent reduction of assembled Complex I retrieved by blue native PAGE in the tissue from these mice. Of note, rotenone completely inhibits the residual respiration of Ndufs4-/- mitochondria, indicating that this Complex I inhibitor is still working in this genetic background. The complete lack of Complex I activity in submitochondrial particles is likely a consequence of the harsh procedure (e.g., sonication) required for their preparation and in no way should be taken as a proof of lack of Complex I in these mitochondria. As correctly pointed out by the authors of the Choi et al. study, “…. Thus, one could argue that partially assembled complex I, although lacking complex I activity and the ability to generate NAD+, could still transfer electrons. This may explain the toxicity of rotenone and MPP+ in Ndufs4-/-; neurons.”

    In conclusion, these findings do not indicate that the residual and putatively unstable Complex I that is formed in these mice is not capable of being affected by these specific inhibitors. On the contrary, rotenone does inhibit respiration and therefore electron transfer at Complex I even in Ndufs4-/- mitochondria. Therefore, it is likely that rotenone and MPTP do not have Complex I independent effects on mitochondria, and that their effect on dopaminergic neuron viability is solely related to Complex I inhibition.

    View all comments by Vanessa Morais