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Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in  pink1  mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other  pink1 -associated phenotypes. We expressed  Saccaromyces cerevisiae  Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt  Ciona intestinalis  AOX, an enzyme that bypasses ETC Complex III and IV, in  pink1  mutant  Drosophila  and find that expression of Ndi1p, but not of AOX, rescues  pink1 -associated defects. Likewise, loss of function of subunits that encode for Complex I–associated proteins displays many of the  pink1 -associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the  parkin  mutant phenotypes. Additionally, unlike  pink1  mutants, fly  parkin  mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in  pink1  mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in  pink1  mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in  pink1 -associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling.

The Yeast Complex I Equivalent NADH Dehydrogenase Rescues pink1 Mutants