in particular, have never been proposed to be rate-limiting for dopamine synthesis, although recent work suggests that some dopamine synthesis may occur in or on mitochondria15. Thus, it remains to be explained how an increase in a complex I subunit leads to increased dopamine in otherwise normal neurons. The work of Alvarez-Fischer et al.1 has important implications for the pathogenesis and treatment of Parkinson’s disease. If Engrailed can protect nigrostriatal neurons from multiple causes of degeneration, why doesn’t it do so as the disease process is initiated? The incidence of Parkinson’s disease is age-related. Does neuronal expression of Engrailed decline with age? What but the amount of dopamine in the Engrailedinjected hemisphere actually exceeded control values from mice that did not receive the toxin. To further explore this, the authors then infused Engrailed into substantia nigra of normal control mice and found a 50% increase in striatal dopamine without a change in nigrostriatal neuron number. Although it would be easy to dismiss this as an independent transcriptional or translational effect of Engrailed on dopamine synthesis, it was shown that this effect depends on Ndufs1 translation. Although this result seems clear-cut, its mechanism is not, and the authors offer no explanation. After all, mitochondrial energy metabolism in general, and complex I activity regulates local levels of Engrailed, and is this disrupted in Parkinson’s disease? Is endogenous Engrailed damaged or inactivated by the ongoing oxidative stress associated with mitochondrial impairment in Parkinson’s disease? In terms of treatment, Engrailed holds immense potential. Not only might it protect the vulnerable nigrostriatal neurons, but it may also induce them to produce more dopamine and thereby decrease the need for conventional dopamine replacement therapy and its attendant side effects. Complex I is the most complicated component of the electron transport chain, being composed of about 45 subunits derived from two interacting genomes. It is no surprise that its regulation is intricate. Yet there will no doubt be more surprises as we learn how Engrailed and other factors regulate complex I. It is already apparent that Engrailed is complex too.